3-aminoalkyl-1,4-diazepan-2-one melanocortin-5-receptor antagonists

ABSTRACT

The present invention provides compounds of Formula (I) that are useful for modulating the biological activity of the melanocortin-5 receptor (MC5R). Compounds of this invention can be used to treat diseases and/or conditions in which downregulation of MC5R is beneficial. Such diseases and/or conditions include, but are not limited to, acne, seborrhea, seborrheic dermatitis, cancer, and inflammatory diseases.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of U.S. patentapplication Ser. No. 12/391,720, now allowed, which claims the benefitof U.S. Provisional Application No. 61/032,912, filed on Feb. 29, 2008,and U.S. Provisional Application No. 61/032,894, filed on Feb. 29, 2008,each of which are incorporated by reference in their entirety.

FIELD OF THE INVENTION

The present invention relates to the field of melanocortin-5 receptorantagonists. In particular the present invention relates to a family of1,4-diazepan-2-ones and derivatives thereof that are antagonists of themelanocortin-5 receptor. The invention also relates to pharmaceuticalcompositions containing these compounds.

BACKGROUND OF THE INVENTION

The melanocortin-5 receptor (MC5R) is a G-protein coupled receptor(GPCR) belonging to the family of melanocortin receptors. There are fivemelanocortin receptors that have been isolated and cloned to date: MC1R,MC2R, MC3R, MC4R and MC5R. The melanocortin receptors participate in avariety of physiologic functions, providing a number of opportunitiesfor therapeutic intervention in physiologic processes through alteration(i.e., a statistically significant increase or decrease) or modulation(e.g., up-regulation or down-regulation) of melanocortin receptorsignalling activity.

Reviews of the melanocortin receptors, and their potential as targetsfor therapy have been published (Wikberg 2001; Bohm 2006). Themelanocortin receptor family members are regulated by natural peptideagonists such as ACTH and the melanocyte-stimulating hormones (α-, β-,γ-MSH) derived from pro-opiomelanocortin (POMC) and by peptideantagonists such as Agouti signal protein (ASP) and Agouti-relatedpeptide (AGRP). The MC1R is widely expressed and is associated withpigmentation in melanocytes and with inflammation responses in manycells involved in the immune system. The MC2R differs from the othermelanocortin receptors in that it binds only ACTH but not MSH ligands.It is highly expressed in the adenal gland and controls corticosteroidsynthesis. The MC3R is found in the brain, but also elsewhere in thebody, and appears to play a role in the regulation of energyhomeostasis, and possibly sexual dysfunction. The MC4R is found almostexclusively in the brain, with some reports of its presence elsewhere.It has been strongly associated with feeding control, and alsoimplicated with sexual desire. The MC5R is widely expressed inperipheral tissues, particularly in the exocrine glands, with somereceptor also expressed in the brain. Given the breadth of activityassociated with the melanocortin receptors it is desirable when seekingto target one of these receptors to do so selectively in order to avoidside effects associated with antagonism or agonism of another receptorin this family.

The MC5R has been cloned and expressed from multiple species, includinghumans in 1993 (though called MC2 in this paper) (Chhajlani 1993), ratin 1994 (Griffon 1994) mice in 1994 (Gantz 1994; Labbé 1994) and in 1995(Fathi 1995), canine (Houseknecht 2003), rhesus monkey (Huang 2000),sheep (Barrett 1994), zebrafish (Ringholm 2002), goldfish(Cerdá-Reverter 2003), spiny dogfish (Klovins 2004), rainbow trout(Haitina 2004), and chicken (Ling 2004), with the MC5R gene alsoidentified in pig (Kim 2000). Patents covering the MC5R sequence inhumans (Wikberg 2002), mice (Yamada 1997), rhesus monkey (Fong 2003) anddogs (Houseknecht 2003) have been published.

The MC5R has been implicated in regulating sebum secretion by a numberof studies, as summarized in 2006 (Zhang 2006). Mice lacking MC5R havereduced sebum production, as evidenced by a marked in ability to shedwater from their fur, and a reduced quantity of sebum isolated fromtheir hair. Significantly, these mice were otherwise generally healthy,with no readily visible abnormalities (appearance, behaviour, growth,muscle mass, adipose mass, reproduction, basal and stress-inducedcorticosterone, glucose and insulin levels) (Chen 1997). Further studieshave identified reductions in pheromones, causing alterations inaggressive behaviours between mice (Caldwell 2002; Morgan 2004a; Morgan2004b; Morgan 2006). Mice in which the POMC-derived peptide nativeligands of MC5R have been knocked out show a similar phenotype (Yaswen1999). Rats injected with α-MSH had 30-37% increased rates of sebumproduction, while removal of the neurointermediate lobe (the source ofMSH) caused a 35% decrease in sebum secretion, which was restored uponadministration of α-MSH (Thody 1973). A synergistic effect between α-MSHand testosterone was observed in rats, with testosterone increasingsebaceous gland and cell volumes (presumably via increasedproliferation), α-MSH increasing dermal lipogenesis, and the combinationincreasing sebum secretion (Thody 1975a; Thody 1975b).

At a cellular level human sebocytes have been shown to express MC5R, viadetection of MC5R transcripts in micro-dissected sebaceous glands(Thiboutot 2000), detection of MC5R in human facial sebaceous glands byimmunostaining (Hatta 2001), detection of MC5R mRNA and MC5R in humansebaceous glands, cultured human sebocytes and rat preputial cells(Thiboutot 2000) and detection of MC5R as punctate particles withinsebaceous glands by staining with polyclonal antibodies, seen indifferentiated but not undifferentiated sebocytes (Zhang 2006). MC5RmRNA was also detected in sebaceous glands from the skin of wild-typemice, but not in skin sections of the MC5R-knockout mice (Chen 1997).Treatment of human sebocytes with cholera toxin (ChT), bovine pituitaryextract (BPE), α-MSH or NDP-MSH increases lipid droplet formation,squalene synthesis, and MC5R expression (Zhang 2003; Zhang 2006), Whileboth MC1R and MC5R have been detected in sebaceous cells, treatment ofprimary human sebocyte cell culture with NDP-MSH or BPE caused asubstantial increase in human MC5R expression compared to serum-freeconditions, correlating with sebocyte differentiation. Immortalizedsebaceous cell lines (SZ-95, TSS-1 and SEB-1) also show MC5R expression(Jeong 2007; Smith 2007a; Phan 2007). These studies suggest that MC5Rantagonists could be useful in reducing sebum secretion in mammals andhence in treating conditions associated with excess sebum secretion.

A family of 1,2,4-thiadiazole derivatives with MC5R antagonist activity(138-320 nM) were found to reduce sebum formation both in human sebocytecell cultures and when applied topically to human skin grafted ontoimmunodeficient mice (Eisinger 2003a-d; 2006a,b).

Excessive sebum secretion, or seborrhoea, is a common affliction.Sebaceous glands occur over most of the body, with dense concentrationsof large glands on the face, scalp and upper trunk (Simpson and Cunliffep 43.1). Sebaceous secretion is dependent in part on androgenichormones, possibly partly mediated by 5α-reductase processing oftestosterone to 5α-DHT (dihydrotestosterone). Sebum consists of aspecies-specific mixture of lipids. In humans this consists ofapproximately 58% glycerides, 26% wax esters, 12% squalene, and 4%cholesterol/cholesterol esters (Simpson and Cunliffe p 43.5). Thepresence of squalene is almost exclusively characteristic of humansebum. The function of sebum is not well defined, but it is believed tohave fungistatic properties, and play a role in moisture loss from, andwater repellence of, the epidermis (Simpson and Cunliffe p 43.6; Danby2005; Porter 2001; Shuster 1976; Kligman 1963).

Excessive sebum secretion has been associated with the development ofacne vulgaris. Acne vulgaris is a common disease affecting an estimated80% of the world's population at some stage in their lives. A person ismore likely to develop acne than any other disease, although theseverity varies greatly (Simpson and Cunliffe p 43.16). Acne peaks inprevalence and severity in adolescents aged 14-19 years old, withapproximately 35-40% affected, but in a significant number of patients(7-24%) it persists beyond 25 years of age (Simpson and Cunliffe p43.15). Of patients treated for acne, one study found 80% still hadsymptoms at 30-40 years of age (Simpson and Cunliffe p 43.16). Whileacne is not a life-threatening disease it can have a severe impact on apatient's quality of life (Follador 2006), with one study of severe acnepatients showing similar impact as much more serious chronic medicalconditions such as asthma, epilepsy, diabetes, back pain or arthritis(Mallon 1999).

Four major factors are believed to be involved in the pathogenesis ofacne: (i) increased sebum production (seborrhoea), (ii)hypercornification/blockage of the pilosebaceous duct (comodogenesis),(iii) infection of the duct with P. acnes, and (iv) inflammation of thepilosebaceous duct (Simpson and Cunliffe p 43.15; Williams 2006). Anumber of studies have demonstrated a clear link between increasedproduction of sebum, and the presence and severity of acne (Simpson andCunliffe p 43.17; Youn 2005; Piérard 1987; Harris 1983; Cotterill 1981;Thody 1975c; Pochi 1964). A 2007 study found a correlation between sebumexcretion and development of acne in preadolescent children (Mourelatos2007). Sebum is the main nutrient of P. acnes, thus reduction of sebumwill reduce the subsequent bacterial infection and inflammationresponse.

Androgenic sex hormones appear to play a role in the development ofacne, with strong correlations with sebum production (Makrantonaki2007). Two oral contraceptive pills are approved by the FDA for thetreatment of acne vulgaris (Harper 2005), and these compounds appear toact by reducing androgen mediated sebum formation. Diet (Cordain 2005;Smith 2007b), stress (Zouboulis 2004) and genetic factors (Goulden 1999;Bataille 2006) also may play a role in acne, again potentially viaincreased sebum production.

Current treatments for acne vulgaris focus predominantly on treating theinfection and inflammation stages of the disease, with a large number ofdifferent formulations of topical antibiotics (e.g. benzoyl peroxide,tetracycline, erythromycin, clindamycin) and retinoids (e.g. retinoicacid, isotretinoin, adapalene, tazarotene) in use, either alone or incombination; some of these also possess anti-inflammatory action(Simpson and Cunliffe p 43.36-43.38). Many of these treatments are oflimited efficacy, particularly for severe cases of acne. A growingproblem is the development of antibiotic-resistant strains of P. acnes(Simpson and Cunliffe p 43.37, 43.46; Williams 2006). Both topicalretinoids and benzoyl peroxide cause skin irritation, and retinoids cancause photosensitivity (Williams 2006). Oral therapies includeisotretinoin, antibiotics, hormones, and steroids. In females,antiandrogens have been shown to reduce sebum production (byapproximately 40-80%, though with no placebo control group) and improveacne (Simpson and Cunliffe p 43.44; Burke 1984; Goodfellow 1984). Laserand UV-based therapies are gaining acceptance, and are believed to actthrough heating of the sebaceous gland followed by reduction in sebumformation; with reductions in both sebum formation and acne lesionsmeasured (Jih 2006; Bhardwaj 2005). Of the many therapies available foracne, only oral isotretinoin and hormonal therapies act by regulatingthe sebaceous gland to reduce sebum secretion (Clarke 2007).

The most effective acne treatment, oral isotretinoin (13-cis-retinoicacid, Roaccutane, Accutane) was introduced in 1983 and still remains themost clinically effective anti-acne therapy. It is the only knowntreatment with strong sebusuppressive activity, reducing sebum excretionby up to 90% after 8-12 weeks of therapy (60-70% by 2 weeks) (Simpsonand Cunliffe p 43.47; Jones 1983; Goldstein 1982; King 1982). Topicalretinoids, in contrast, have no effect on sebum production. Oralisotretinoin is also anti-inflammatory, reduces comedogenesis, andreduces P. acnes infection. The mechanism of action is still unclear,and metabolites of isotretinoin appear to play a significant role.Isotretinoin induces apoptosis and cell cycle arrest in humanimmortalized SEB-1 sebocyte cell culture (Nelson 2006). Unfortunately,oral isotretinoin has serious side effects; most significantly it is ateratogen and requires a registration program for use in the USA. TheFDA has issued a warning against online purchases of isotretinoin. Bloodtesting for fasting lipids and liver function is also recommended duringtreatment (Williams 2006). Isotretinoin has been implicated (though notsubstantively) with adverse psychological effects, including suicide anddepression (Marqueling 2005).

Other forms of acne, such as acne conglobata or acne fulminans, may alsorespond to a sebum-reducing agent. Seborrhoea, or excessive skin oilproduction, is often associated with severe acne. Seborrheic dermatitis(SD) is a skin disease associated with sebum-rich areas of the scalp,face and trunk with scaly, flaky, itchy red skin affecting 3-5% of thepopulation; dandruff represents a mild form of this dermatitis affecting15-20% of the population. Seborrhoea and SD appear more common inpatients with Parkinson's disease or mood disorders (facial paralysis,supraorbital injury, poliomyelitis, syringomyelia, quadriplegia,unilateral injury to the ganglion Gasser and those with HIV/AIDS)(Plewig 1999). Studies have shown that seborrheic dermatitis is alsoassociated with chronic alcoholic pancreatitis, hepatitis C virus andvarious cancers. It is also common in patients with genetic disorders,such as Down's syndrome, Hailey-Hailey disease and cardio-faciocutaneous syndrome (Gupta 2004). MC5R antagonists may be useful fortreating these indications.

Although rare, a variety of tumours involving sebaceous glands orsebaceous cells have been described (e.g. Ide 1999; Mariappan 2004;Kruse 2003). Muir-Torre syndrome consists of sebaceous gland adenomasassociated with an internal adenocarcinoma (usually colon, breast, ovaryor prostate). Preventing sebaceous cell differentiation may provide aneffective treatment for arresting tumour growth. Oral isotretinoin hasbeen used for this purpose (Graefe 2000). Sebaceous hyperplasia is abenign hyperplasia of the sebaceous glands, generating yellowish smallpapules on the skin surface, usually the face. The disease is associatedwith excessive undifferentiated sebocyte proliferation, but notexcessive sebum formation. Ectopic sebaceous glands (Fordyce spots) aresimilar yellow papules found in the mouth or on the penile shaft. Bothrespond to oral isotretinoin. A compound that reduced sebocyteproliferation could be an effective treatment.

α-MSH shows immunosuppressive effects in humans, suppressing a varietyof inflammation responses, and the MC5R has been implicated in theseimmunomodulating activities. MC5R mRNA was found to be expressed at highlevels in human CD4+ T helper (Th) cells and in moderate levels in otherhuman peripheral blood leukocytes (Andersen 2005). In mice, MC5R wasdetected in the lymphoid organs (Labbé, 1994), and MC5R was found on thesurface of mouse pro-B-lymphocyte cells where it appears to mediateα-MSH activation of the JAK2 signalling pathway, enhancing cellularproliferation (Buggy 1998). Induction of CD25+ CD4+ regulatory T-cellsby α-MSH also appears to be through MC5R (Taylor 2001).

For the reasons described above it would be desirable to provide MC5Rantagonists that could be used in a number of therapeutic areas.Therapeutic regulation of biological signal transduction includesmodulation of MC5R-mediated cellular events including, inter alia,inhibition or potentiation of interactions among MC5R-binding andactivating or deactivating molecules, or of other agents that regulateMC5R activities. An increased ability to so regulate MC5R may facilitatethe development of methods for modulating sebum secretion or otherbiological processes, and for treating conditions associated with suchpathways such as acne as described above.

The present applicants have now identified a family of1,4-diazepan-2-ones that display MC5R antagonist activity which shouldbe useful in treating MC5R related conditions.

SUMMARY OF THE INVENTION

The present invention provides compounds of formula (I):

wherein:

Y is a group of formula —(CR⁹R¹⁰)_(n)—;

X is selected from the group consisting —C(═O)—, —OC(═O)—, —NHC(═O)—,—(CR¹¹R¹²)_(s), and —S(═O)₂—;

Z is a group of formula —(CR¹³R¹⁴)_(q)—;

R¹ is selected from the group consisting of H, optionally substitutedC₁-C₁₂alkyl, optionally substituted C₂-C₁₂alkenyl, optionallysubstituted C₂-C₁₂alkynyl, optionally substituted C₁-C₁₂heteroalkyl,optionally substituted C₃-C₁₂cycloalkyl, optionally substitutedC₂-C₁₂heterocycloalkyl, optionally substituted C₆-C₁₈aryl, andoptionally substituted C₁-C₁₈heteroaryl;

R² and R³ are each independently selected from the group consisting ofH, optionally substituted C₁-C₁₂alkyl, optionally substitutedC₂-C₁₂alkenyl, optionally substituted C₂-C₁₂alkynyl, optionallysubstituted C₁-C₁₂heteroalkyl, optionally substituted C₃-C₁₂cycloalkyl,optionally substituted C₂-C₁₂heterocycloalkyl, optionally substitutedC₆-C₁₈aryl, and optionally substituted C₁-C₁₈heteroaryl;

R^(4a) is selected from the group consisting of H, optionallysubstituted C₁-C₁₂alkyl, optionally substituted C₂-C₁₂alkenyl,optionally substituted C₂-C₁₂alkynyl, optionally substitutedC₁-C₁₂heteroalkyl, optionally substituted C₃-C₁₂cycloalkyl, optionallysubstituted C₂-C₁₂heterocycloalkyl, optionally substituted C₆-C₁₈aryl,optionally substituted C₁-C₁₈heteroaryl, C(═O)R¹⁵, C(═O)NR¹⁵R¹⁶,C(═O)OR¹⁵, SO₂R¹⁵, C(═O)H, —C(═NR¹⁵)—NR¹⁶R¹⁷, and OR¹⁵,

R^(4b) is selected from the group consisting of H, optionallysubstituted C₁-C₁₂alkyl, optionally substituted C₂-C₁₂alkenyl,optionally substituted C₂-C₁₂alkynyl, optionally substitutedC₁-C₁₂heteroalkyl, optionally substituted C₃-C₁₂cycloalkyl, optionallysubstituted C₂-C₁₂heterocycloalkyl, optionally substituted C₆-C₁₈aryl,optionally substituted C₁-C₁₈heteroaryl, C(═O)R¹⁵, C(═O)NR¹⁵R¹⁶,C(═O)OR¹⁵, or

R^(4a) and R^(4b) when taken together with the nitrogen atom to whichthey are attached form an optionally substituted heterocyclic moiety, or

one of R^(4a) and R^(4b) when taken together with any of R¹³ or R¹⁴forms an optionally substituted heterocyclic group;

each R^(5a) and R^(5b) are independently selected from the groupconsisting of H, halogen, C₁-C₁₂alkyl, C₁-C₁₂hydroxyalkyl andC₁-C₁₂haloalkyl, or

one or more of R^(5a) and R^(5b) when taken together with one or more ofR⁶, R⁷ and R⁸ and the atoms to which they are attached form a moietyselected from the group consisting of an optionally substitutedC₃-C₁₂cycloalkyl, optionally substituted C₂-C₁₂ heterocycloalkyl,optionally substituted C₆-C₁₈aryl, and optionally substitutedC₁-C₁₈heteroaryl;

R⁶, R⁷ and R⁸ are each independently selected from the group consistingof H, halogen, hydroxy, optionally substituted C₁-C₁₂alkyl, optionallysubstituted C₂-C₁₂alkenyl, optionally substituted C₂-C₁₂alkynyl,optionally substituted C₁-C₁₂ heteroalkyl, optionally substituted C₁-C₁₀heteroalkenyl, optionally substituted C₃-C₁₂cycloalkyl, optionallysubstituted C₂-C₁₂ heterocycloalkyl, optionally substituted C₆-C₁₈aryl,optionally substituted C₁-C₁₈heteroaryl, optionally substituted amino,optionally substituted carboxy, C₁-C₁₂alkyloxy, and optionallysubstituted thio, or

(a) when taken together with the carbon atom to which they are attachedtwo or more of R⁶, R⁷ and R⁸ form a moiety selected from the groupconsisting of optionally substituted C₂-C₁₂alkenyl, optionallysubstituted C₃-C₁₂cycloalkyl, optionally substitutedC₂-C₁₂heterocycloalkyl, optionally substituted C₆-C₁₈aryl, andoptionally substituted C₁-C₁₈heteroaryl, or

(b) one or more of R⁶, R⁷ and R⁸ when taken together with one or more ofR^(5a) and R^(5b) and the atoms to which they are attached form a moietyselected from the group consisting of an optionally substitutedC₃-C₁₂cycloalkyl, optionally substituted C₂-C₁₂ heterocycloalkyl,optionally substituted C₆-C₁₈aryl, and optionally substitutedC₁-C₁₈heteroaryl;

each R⁹ and R¹⁰ is independently selected from the group consisting of Hand optionally substituted C₁-C₁₂alkyl;

each R¹¹ and R¹² is independently selected from the group consisting ofH, and optionally substituted C₁-C₁₂alkyl;

each R¹³ and R¹⁴ is independently selected from the group consisting ofH, halogen, OH, C₁-C₁₂alkyl, C₆-C₁₈aryl, C₁-C₁₂haloalkyl,C₁-C₁₂hydroxyalkyl, C₁-C₁₂alkyloxy and C₁-C₁₂haloalkyloxy, or

when taken together with the carbon to which they are attached R¹³ andR¹⁴ form an optionally substituted C₃-C₁₂cycloalkyl, or an optionallysubstituted C₁-C₁₂heterocycloalkyl group, or

one of R¹³ and R¹⁴ when taken together with one of R^(4a), and R^(4b)form an optionally substituted heterocyclic group;

each R¹⁵, R¹⁶, and R¹⁷ is independently selected from the groupconsisting of H, optionally substituted C₁-C₁₂alkyl, optionallysubstituted C₁-C₁₂heteroalkyl, optionally substituted C₃-C₁₂cycloalkyl,optionally substituted C₆-C₁₈aryl, and optionally substitutedC₁-C₁₈heteroaryl, or

any two of R¹⁵, R¹⁶ and R¹⁷ when taken together with the atoms to whichthey are attached form an optionally substituted cyclic group;

n is an integer selected from the group consisting of 1, 2, 3 and 4;

q is an integer selected from the group consisting of 0, 1, 2, 3, 4, and5;

r is an integer selected from the group consisting of 1, 2, 3, and 4;

s is an integer selected from the group consisting of 1, 2, 3, and 4;

or a pharmaceutically acceptable salt or prodrug thereof.

The invention also relates to pharmaceutical compositions including acompound of the invention with a pharmaceutically acceptable carrier,diluent or excipient.

DETAILED DESCRIPTION OF THE INVENTION

In this specification a number of terms are used which are well known toa skilled addressee. Nevertheless for the purposes of clarity a numberof terms will be defined.

As used herein, the term “unsubstituted” means that there is nosubstituent or that the only substituents are hydrogen.

The term “optionally substituted” as used throughout the specificationdenotes that the group may or may not be further substituted or fused(so as to form a condensed polycyclic system), with one or morenon-hydrogen substituent groups. In certain embodiments the substituentgroups are one or more groups independently selected from the groupconsisting of halogen, ═O, ═S, —CN, —NO₂, —CF₃, —OCF₃, alkyl, alkenyl,alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl,cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl,cycloalkylalkyl, heterocycloalkylalkyl, heteroarylalkyl, arylalkyl,cycloalkylalkenyl, heterocycloalkylalkenyl, arylalkenyl,heteroarylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl,arylheteroalkyl, heteroarylheteroalkyl, hydroxy, hydroxyalkyl, alkyloxy,alkyloxyalkyl, alkyloxycycloalkyl, alkyloxyheterocycloalkyl,alkyloxyaryl, alkyloxyheteroaryl, alkyloxycarbonyl, alkylaminocarbonyl,alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy,heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, phenoxy, benzyloxy,heteroaryloxy, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl,arylamino, sulfonylamino, sulfinylamino, sulfonyl, alkylsulfonyl,arylsulfonyl, aminosulfonyl, sulfinyl, alkylsulfinyl, arylsulfinyl,aminosulfinylaminoalkyl, —C(═O)OH, —C(═O)R^(a), —C(═O)OR^(a),C(═O)NR^(a)R^(b), C(═NOH)R^(a), C(═NR^(a))NR^(b)R^(c), NR^(a)R^(b),NR^(a)C(═O)R^(b), NR^(a)C(═O)OR^(b), NR^(a)C(═O)NR^(b)R^(c),NR^(a)C(═NR^(b))NR^(c)R^(d), NR^(a)SO₂R^(b), —SR^(a), SO₂NR^(a)R^(b),—OR^(a)C(═O)NR^(a)R^(b), OC(═O)R^(a) and acyl,

wherein R^(a), R^(b), R^(c) and R^(d) are each independently selectedfrom the group consisting of H, C₁-C₁₂ alkyl, C₁-C₁₂ haloalkyl, C₂-C₁₂alkenyl, C₂-C₁₂ alkynyl, C₁-C₁₀ heteroalkyl, C₃-C₁₂ cycloalkyl, C₃-C₁₂cycloalkenyl, C₁-C₁₂ heterocycloalkyl, C₁-C₁₂ heterocycloalkenyl,C₆-C₁₈aryl, C₁-C₁₈heteroaryl, and acyl, or any two or more of R^(a),R^(b), R^(c) and R^(d), when taken together with the atoms to which theyare attached form a heterocyclic ring system with 3 to 12 ring atoms.

In one embodiment each optional substituent is independently selectedfrom the group consisting of: halogen, ═O, ═S, —CN, —NO₂, —CF₃, —OCF₃,alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl,heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl,heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkyloxy,alkyloxyalkyl, alkyloxyaryl, alkyloxyheteroaryl, alkenyloxy, alkynyloxy,cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy,heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl,heteroarylalkyl, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl,arylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl,aminoalkyl, —COOH, —SH, and acyl.

Examples of particularly suitable optional substituents include F, Cl,Br, I, CH₃, CH₂CH₃, OH, OCH₃, CF₃, OCF₃, NO₂, NH₂, and CN.

In the definitions of a number of substituents below it is stated that“the group may be a terminal group or a bridging group”. This isintended to signify that the use of the term is intended to encompassthe situation where the group is a linker between two other portions ofthe molecule as well as where it is a terminal moiety. Using the termalkyl as an example, some publications would use the term “alkylene” fora bridging group and hence in these other publications there is adistinction between the terms “alkyl” (terminal group) and “alkylene”(bridging group). In the present application no such distinction is madeand most groups may be either a bridging group or a terminal group.

Several terms are prefaced by the modifier indicating the number ofcarbon atoms present in the moiety. For example, the modifier “C₁-C₆” infront of the term “alkyl” indicates that the alkyl moiety has from 1 to6 carbon atoms. Further, the modifier “C₁-C₁₈” in front of the term“heteroaryl” indicates that the heteroaromatic ring may have from 1 to18 carbon atoms as part of the total number of atoms in the ring system.

“Acyl” means an R—C(═O)— group in which the R group may be an alkyl,cycloalkyl, heterocycloalkyl, aryl or heteroaryl group as definedherein. Examples of acyl include acetyl and benzoyl. The group may be aterminal group or a bridging group. If the group is a terminal group itis bonded to the remainder of the molecule through the carbonyl carbon.

“Acylamino” means an R—C(═O)—NH— group in which the R group may be analkyl, cycloalkyl, heterocycloalkyl; aryl or heteroaryl group as definedherein. The group may be a terminal group or a bridging group. If thegroup is a terminal group it is bonded to the remainder of the moleculethrough the nitrogen atom.

“Alkenyl” as a group or part of a group denotes an aliphatic hydrocarbongroup containing at least one carbon-carbon double bond and which may bestraight or branched preferably having 2-14 carbon atoms, morepreferably 2-12 carbon atoms, most preferably 2-6 carbon atoms, in thenormal chain. The group may contain a plurality of double bonds in thenormal chain and the orientation about each is independently E or Z.Exemplary alkenyl groups include, but are not limited to, ethenyl,propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl and nonenyl. Thegroup may be a terminal group or a bridging group.

“Alkenyloxy” refers to an alkenyl-O— group in which alkenyl is asdefined herein. Preferred alkenyloxy groups are C₁-C₆ alkenyloxy groups.The group may be a terminal group or a bridging group. If the group is aterminal group it is bonded to the remainder of the molecule through theoxygen atom.

“Alkyl” as a group or part of a group refers to a straight or branchedaliphatic hydrocarbon group, preferably a C₁-C₁₄ alkyl, more preferablya C₁-C₁₀ alkyl, most preferably C₁-C₆ unless otherwise noted. Examplesof suitable straight and branched C₁-C₆ alkyl substituents includemethyl, ethyl, n-propyl, 2-propyl, n-butyl, sec-butyl, t-butyl, hexyl,and the like. The group may be a terminal group or a bridging group.

“Alkylamino” includes both mono-alkylamino and dialkylamino, unlessspecified. “Mono-alkylamino” means a Alkyl-NH— group, in which alkyl isas defined herein. “Dialkylamino” means a (alkyl)₂N— group, in whicheach alkyl may be the same or different and are each as defined hereinfor alkyl. The alkyl group is preferably a C₁-C₆ alkyl group. The groupmay be a terminal group or a bridging group. If the group is a terminalgroup it is bonded to the remainder of the molecule through the nitrogenatom.

“Alkylaminocarbonyl” refers to a group of the formula(Alkyl)_(x)(H)_(y)NC(═O)— in which x is 1 or 2, and the sum of x+y=2.The group may be a terminal group or a bridging group. If the group is aterminal group it is bonded to the remainder of the molecule through thecarbonyl carbon.

“Alkyloxy” refers to an alkyl-O— group in which alkyl is as definedherein. Preferably the alkyloxy is a C₁-C₆alkyloxy. Examples include,but are not limited to, methoxy and ethoxy. The group may be a terminalgroup or a bridging group.

“Alkyloxyalkyl” refers to an alkyloxy-alkyl- group in which the alkyloxyand alkyl moieties are as defined herein. The group may be a terminalgroup or a bridging group. If the group is a terminal group it is bondedto the remainder of the molecule through the alkyl group.

“Alkyloxyary” refers to an alkyloxy-aryl- group in which the alkyloxyand aryl moieties are as defined herein. The group may be a terminalgroup or a bridging group. If the group is a terminal group it is bondedto the remainder of the molecule through the aryl group.

“Alkyloxycarbonyl” refers to an alkyl-O—C(═O)— group in which alkyl isas defined herein. The alkyl group is preferably a C₁-C₆ alkyl group.Examples include, but are not limited to, methoxycarbonyl andethoxycarbonyl. The group may be a terminal group or a bridging group.If the group is a terminal group it is bonded to the remainder of themolecule through the carbonyl carbon.

“Alkyloxycycloalkyl” refers to an alkyloxy-cycloalkyl- group in whichthe alkyloxy and cycloalkyl moieties are as defined herein. The groupmay be a terminal group or a bridging group. If the group is a terminalgroup it is bonded to the remainder of the molecule through thecycloalkyl group.

“Alkyloxyheteroary” refers to an alkyloxy-heteroaryl- group in which thealkyloxy and heteroaryl moieties are as defined herein. The group may bea terminal group or a bridging group. If the group is a terminal groupit is bonded to the remainder of the molecule through the heteroarylgroup.

“Alkyloxyheterocycloalkyl” refers to an alkyloxy-heterocycloalkyl- groupin which the alkyloxy and heterocycloalkyl moieties are as definedherein. The group may be a terminal group or a bridging group. If thegroup is a terminal group it is bonded to the remainder of the moleculethrough the heterocycloalkyl group.

“Alkylsulfinyl” means an alkyl-S—(═O)— group in which alkyl is asdefined herein. The alkyl group is preferably a C₁-C₆ alkyl group.Exemplary alkylsulfinyl groups include, but not limited to,methylsulfinyl and ethylsulfinyl. The group may be a terminal group or abridging group. If the group is a terminal group it is bonded to theremainder of the molecule through the sulfur atom.

“Alkylsulfonyl” refers to an alkyl-S(═O)₂— group in which alkyl is asdefined above. The alkyl group is preferably a C₁-C₆ alkyl group.Examples include, but not limited to methylsulfonyl and ethylsulfonyl.The group may be a terminal group or a bridging group. If the group is aterminal group it is bonded to the remainder of the molecule through thesulfur atom.

“Alkynyl” as a group or part of a group means an aliphatic hydrocarbongroup containing a carbon-carbon triple bond and which may be straightor branched preferably having from 2-14 carbon atoms, more preferably2-12 carbon atoms, more preferably 2-6 carbon atoms in the normal chain.Exemplary structures include, but are not limited to, ethynyl andpropynyl. The group may be a terminal group or a bridging group.

“Alkynyloxy” refers to an alkynyl-O— group in which alkynyl is asdefined herein. Preferred alkynyloxy groups are C₁-C₆ alkynyloxy groups.The group may be a terminal group or a bridging group. If the group is aterminal group it is bonded to the remainder of the molecule through theoxygen atom.

“Aminoalkyl” means an NH₂-alkyl- group in which the alkyl group is asdefined herein. The group may be a terminal group or a bridging group.If the group is a terminal group it is bonded to the remainder of themolecule through the alkyl group.

“Aminosulfonyl” means an NH₂—S(═O)₂— group. The group may be a terminalgroup or a bridging group. If the group is a terminal group it is bondedto the remainder of the molecule through the sulfur atom.

“Aryl” as a group or part of a group denotes (i) an optionallysubstituted monocyclic, or fused polycyclic, aromatic carbocycle (ringstructure having ring atoms that are all carbon) preferably having from5 to 12 atoms per ring. Examples of aryl groups include phenyl,naphthyl, and the like; (ii) an optionally substituted partiallysaturated bicyclic aromatic carbocyclic moiety in which a phenyl and aC₅₋₇ cycloalkyl or C₅₋₇ cycloalkenyl group are fused together to form acyclic structure, such as tetrahydronaphthyl, indenyl or indanyl. Thegroup may be a terminal group or a bridging group. Typically an arylgroup is a C₆-C₁₈ aryl group.

“Arylalkenyl” means an aryl-alkenyl- group in which the aryl and alkenylare as defined herein. Exemplary arylalkenyl groups include phenylallyl.The group may be a terminal group or a bridging group. If the group is aterminal group it is bonded to the remainder of the molecule through thealkenyl group.

“Arylalkyl” means an aryl-alkyl- group in which the aryl and alkylmoieties are as defined herein. Preferred arylalkyl groups contain aC₁₋₅ alkyl moiety. Exemplary arylalkyl groups include benzyl, phenethyl,1-naphthalenemethyl and 2-naphthalenemethyl. The group may be a terminalgroup or a bridging group. If the group is a terminal group it is bondedto the remainder of the molecule through the alkyl group.

“Arylalkyloxy” refers to an aryl-alkyl-O— group in which the alkyl andaryl are as defined herein. The group may be a terminal group or abridging group. If the group is a terminal group it is bonded to theremainder of the molecule through the oxygen atom.

“Arylamino” includes both mono-arylamino and di-arylamino unlessspecified. Mono-arylamino means a group of formula arylNH—, in whicharyl is as defined herein. Di-arylamino means a group of formula(aryl)₂N— where each aryl may be the same or different and are each asdefined herein for aryl. The group may be a terminal group or a bridginggroup. If the group is a terminal group it is bonded to the remainder ofthe molecule through the nitrogen atom.

“Arylheteroalkyl” means an aryl-heteroalkyl- group in which the aryl andheteroalkyl moieties are as defined herein. The group may be a terminalgroup or a bridging group. If the group is a terminal group it is bondedto the remainder of the molecule through the heteroalkyl group.

“Aryloxy” refers to an aryl-O— group in which the aryl is as definedherein. Preferably the aryloxy is a C₆-C₁₈aryloxy, more preferably aC₆-C₁₀aryloxy. The group may be a terminal group or a bridging group. Ifthe group is a terminal group it is bonded to the remainder of themolecule through the oxygen atom.

“Arylsulfonyl” means an aryl-S(═O)₂— group in which the aryl group is asdefined herein. The group may be a terminal group or a bridging group.If the group is a terminal group it is bonded to the remainder of themolecule through the sulfur atom.

A “bond” is a linkage between atoms in a compound or molecule. The bondmay be a single bond, a double bond, or a triple bond.

“Cyclic group” refers to saturated, partially unsaturated or fullyunsaturated monocyclic, bicyclic or polycyclic ring system. Examples ofcyclic groups include cycloalkyl, cycloalkenyl and aryl.

“Cycloalkenyl” means a non-aromatic monocyclic or multicyclic ringsystem containing at least one carbon-carbon double bond and preferablyhaving from 5-10 carbon atoms per ring. Exemplary monocycliccycloalkenyl rings include cyclopentenyl, cyclohexenyl or cycloheptenyl.The cycloalkenyl group may be substituted by one or more substituentgroups. The group may be a terminal group or a bridging group.

“Cycloalkyl” refers to a saturated monocyclic or fused or spiropolycyclic, carbocycle preferably containing from 3 to 9 carbons perring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and thelike, unless otherwise specified. It includes monocyclic systems such ascyclopropyl and cyclohexyl, bicyclic systems such as decalin, andpolycyclic systems such as adamantane. The group may be a terminal groupor a bridging group.

“Cycloalkylalkyl” means a cycloalkyl-alkyl- group in which thecycloalkyl and alkyl moieties are as defined herein. Exemplarymonocycloalkylalkyl groups include cyclopropylmethyl, cyclopentylmethyl,cyclohexylmethyl and cycloheptylmethyl. The group may be a terminalgroup or a bridging group. If the group is a terminal group it is bondedto the remainder of the molecule through the alkyl group.

“Cycloalkylalkenyl” means a cycloalkyl-alkenyl- group in which thecycloalkyl and alkenyl moieties are as defined herein. The group may bea terminal group or a bridging group. If the group is a terminal groupit is bonded to the remainder of the molecule through the alkenyl group.

“Cycloalkylheteroalkyl” means a cycloalkyl-heteroalkyl- group in whichthe cycloalkyl and heteroalkyl moieties are as defined herein. The groupmay be a terminal group or a bridging group. If the group is a terminalgroup it is bonded to the remainder of the molecule through theheteroalkyl group.

“Cycloalkyloxy” refers to a cycloalkyl-O— group in which cycloalkyl isas defined herein. Preferably the cycloalkyloxy is a C₁-C₆cycloalkyloxy.Examples include, but are not limited to, cyclopropanoxy andcyclobutanoxy. The group may be a terminal group or a bridging group. Ifthe group is a terminal group it is bonded to the remainder of themolecule through the oxygen atom.

“Cycloalkenyloxy” refers to a cycloalkenyl-O— group in which thecycloalkenyl is as defined herein. Preferably the cycloalkenyloxy is aC₁-C₆cycloalkenyloxy. The group may be a terminal group or a bridginggroup. If the group is a terminal group it is bonded to the remainder ofthe molecule through the oxygen atom.

“Haloalkyl” refers to an alkyl group as defined herein in which one ormore of the hydrogen atoms has been replaced with a halogen atomselected from the group consisting of fluorine, chlorine, bromine andiodine. A haloalkyl group typically has the formulaC_(n)H_((2n+1−m))X_(m) wherein each X is independently selected from thegroup consisting of F, Cl, Br and I. In groups of this type n istypically from 1 to 10, more preferably from 1 to 6, most preferably 1to 3. m is typically 1 to 6, more preferably 1 to 3. Examples ofhaloalkyl include fluoromethyl, difluoromethyl and trifluoromethyl.

“Haloalkenyl” refers to an alkenyl group as defined herein in which oneor more of the hydrogen atoms has been replaced with a halogen atomindependently selected from the group consisting of F, Cl, Br and I.

“Haloalkynyl” refers to an alkynyl group as defined herein in which oneor more of the hydrogen atoms has been replaced with a halogen atomindependently selected from the group consisting of F, Cl, Br and I.

“Halogen” represents chlorine, fluorine, bromine or iodine.

“Heteroalkyl” refers to a straight- or branched-chain alkyl grouppreferably having from 2 to 14 carbons, more preferably 2 to 10 carbonsin the chain, one or more of which has been replaced by a heteroatomselected from S, O, P and N. Exemplary heteroalkyls include alkylethers, secondary and tertiary alkyl amines, amides, alkyl sulfides, andthe like. The group may be a terminal group or a bridging group.

“Heteroaryl” either alone or part of a group refers to groups containingan aromatic ring (preferably a 5 or 6 membered aromatic ring) having oneor more heteroatoms as ring atoms in the aromatic ring with theremainder of the ring atoms being carbon atoms. Suitable heteroatomsinclude nitrogen, oxygen and sulphur. Examples of heteroaryl includethiophene, benzothiophene, benzofuran, benzimidazole, benzoxazole,benzothiazole, benzisothiazole, naphtho[2,3-b]thiophene, furan,isoindolizine, xantholene, phenoxathine, pyrrole, imidazole, pyrazole,pyridine, pyrazine, pyrimidine, pyridazine, tetrazole, indole,isoindole, 1H-indazole, purine, quinoline, isoquinoline, phthalazine,naphthyridine, quinoxaline, cinnoline, carbazole, phenanthridine,acridine, phenazine, thiazole, isothiazole, phenothiazine, oxazole,isoxazole, furazane, phenoxazine, 2-, 3- or 4-pyridyl, 2-, 3-, 4-, 5-,or 8-quinolyl, 1-, 3-, 4-, or 5-isoquinolinyl 1-, 2-, or 3-indolyl, and2-, or 3-thienyl. The group may be a terminal group or a bridging group.

“Heteroarylalkyl” means a heteroaryl-alkyl group in which the heteroaryland alkyl moieties are as defined herein. Preferred heteroarylalkylgroups contain a lower alkyl moiety. Exemplary heteroarylalkyl groupsinclude pyridylmethyl. The group may be a terminal group or a bridginggroup. If the group is a terminal group it is bonded to the remainder ofthe molecule through the alkyl group.

“Heteroarylalkenyl” means a heteroaryl-alkenyl- group in which theheteroaryl and alkenyl moieties are as defined herein. The group may bea terminal group or a bridging group. If the group is a terminal groupit is bonded to the remainder of the molecule through the alkenyl group.

“Heteroarylheteroalkyl” means a heteroaryl-heteroalkyl- group in whichthe heteroaryl and heteroalkyl moieties are as defined herein. The groupmay be a terminal group or a bridging group. If the group is a terminalgroup it is bonded to the remainder of the molecule through theheteroalkyl group.

“Heteroaryloxy” refers to a heteroaryl-O— group in which the heteroarylis as defined herein. Preferably the heteroaryloxy is aC₁-C₁₂heteroaryloxy. The group may be a terminal group or a bridginggroup. If the group is a terminal group it is bonded to the remainder ofthe molecule through the oxygen atom.

“Heterocyclic” refers to saturated, partially unsaturated or fullyunsaturated monocyclic, bicyclic or polycyclic ring system containing atleast one heteroatom selected from the group consisting of nitrogen,sulfur and oxygen as a ring atom. Examples of heterocyclic moietiesinclude heterocycloalkyl, heterocycloalkenyl and heteroaryl.

“Heterocycloalkenyl” refers to a heterocycloalkyl as defined herein butcontaining at least one double bond. The group may be a terminal groupor a bridging group.

“Heterocycloalkyl” refers to a saturated monocyclic, bicyclic, orpolycyclic ring containing at least one heteroatom selected fromnitrogen, sulfur, oxygen, preferably from 1 to 3 heteroatoms in at leastone ring. Each ring is preferably from 3 to 10 membered, more preferably4 to 7 membered. Examples of suitable heterocycloalkyl substituentsinclude pyrrolidyl, tetrahydrofuryl, tetrahydrothiofuranyl, piperidyl,piperazyl, tetrahydropyranyl, morphilino, 1,3-diazapane, 1,4-diazapane,1,4-oxazepane, and 1,4-oxathiapane. The group may be a terminal group ora bridging group.

“Heterocycloalkylalkyl” refers to a heterocycloalkyl-alkyl- group inwhich the heterocycloalkyl and alkyl moieties are as defined herein.Exemplary heterocycloalkylalkyl groups include(2-tetrahydrofuryl)methyl, (2-tetrahydrothiofuranyl)methyl. The groupmay be a terminal group or a bridging group. If the group is a terminalgroup it is bonded to the remainder of the molecule through the alkylgroup.

“Heterocycloalkylalkenyl” refers to a heterocycloalkyl-alkenyl- group inwhich the heterocycloalkyl and alkenyl moieties are as defined herein.The group may be a terminal group or a bridging group. If the group is aterminal group it is bonded to the remainder of the molecule through thealkenyl group.

“Heterocycloalkylheteroalkyl” means a heterocycloalkyl-heteroalkyl-group in which the heterocycloalkyl and heteroalkyl moieties are asdefined herein. The group may be a terminal group or a bridging group.If the group is a terminal group it is bonded to the remainder of themolecule through the heteroalkyl group.

“Heterocycloalkyloxy” refers to a heterocycloalkyl-O— group in which theheterocycloalkyl is as defined herein. Preferably theheterocycloalkyloxy is a C₁-C₆heterocycloalkyloxy. The group may be aterminal group or a bridging group. If the group is a terminal group itis bonded to the remainder of the molecule through the oxygen atom.

“Heterocycloalkenyloxy” refers to a heterocycloalkenyl-O— group in whichheterocycloalkenyl is as defined herein. Preferably theheterocycloalkenyloxy is a C₁-C₆ heterocycloalkenyloxy. The group may bea terminal group or a bridging group. If the group is a terminal groupit is bonded to the remainder of the molecule through the oxygen atom.

“Hydroxyalkyl” refers to an alkyl group as defined herein in which oneor more of the hydrogen atoms has been replaced with an OH group. Ahydroxyalkyl group typically has the formula C_(n)H_((2n+1−x))(OH)_(x).In groups of this type n is typically from 1 to 10, more preferably from1 to 6, most preferably 1 to 3. x is typically 1 to 6, more preferably 1to 3.

“Lower alkyl” as a group means unless otherwise specified, an aliphatichydrocarbon group which may be straight or branched having 1 to 6 carbonatoms in the chain, more preferably 1 to 4 carbons such as methyl,ethyl, propyl (n-propyl or isopropyl) or butyl (n-butyl, isobutyl ortertiary-butyl). The group may be a terminal group or a bridging group.

“Sulfinyl” means an R—S(═O)— group in which the R group may be OH,alkyl, cycloalkyl, heterocycloalkyl; aryl or heteroaryl group as definedherein. The group may be a terminal group or a bridging group. If thegroup is a terminal group it is bonded to the remainder of the moleculethrough the sulfur atom.

“Sulfinylamino” means an R—S(═O)—NH— group in which the R group may beOH, alkyl, cycloalkyl, heterocycloalkyl; aryl or heteroaryl group asdefined herein. The group may be a terminal group or a bridging group.If the group is a terminal group it is bonded to the remainder of themolecule through the nitrogen atom.

“Sulfonyl” means an R—S(═O)₂— group in which the R group may be OH,alkyl, cycloalkyl, heterocycloalkyl; aryl or heteroaryl group as definedherein. The group may be a terminal group or a bridging group. If thegroup is a terminal group it is bonded to the remainder of the moleculethrough the sulfur atom.

“Sulfonylamino” means an R—S(═O)₂—NH— group. The group may be a terminalgroup or a bridging group. If the group is a terminal group it is bondedto the remainder of the molecule through the nitrogen atom.

It is understood that included in the family of compounds of Formula (I)are isomeric forms including diastereoisomers, enantiomers, tautomers,and geometrical isomers in “E” or “Z” configurational isomer or amixture of E and Z isomers. It is also understood that some isomericforms such as diastereomers, enantiomers, and geometrical isomers can beseparated by physical and/or chemical methods and by those skilled inthe art.

Some of the compounds of the disclosed embodiments may exist as singlestereoisomers, racemates, and/or mixtures of enantiomers and/ordiastereomers. All such single stereoisomers, racemates and mixturesthereof, are intended to be within the scope of the subject matterdescribed and claimed.

The present invention includes all pharmaceutically acceptableisotopically-labeled compounds of formula (I) wherein one or more atomshave the same atomic number as, but an atomic mass or mass numberdifferent from, the atomic mass or mass number usually found in nature.

Examples of isotopes suitable for inclusion in the compounds of theinvention include isotopes of hydrogen, such as ²H and ³H, carbon, suchas ¹¹C, ¹³C and ¹⁴C, chlorine, such as ³⁶Cl, fluorine, such ¹⁸F, iodine,such as ¹²³I and ¹²⁵I, nitrogen, such as ¹³N and ¹⁵N, oxygen, such as¹⁵O, ¹⁷O and ¹⁸O, phosphorus, such as ³²P, and sulphur, such as ³⁵S.

Certain isotopically-labeled compounds of formula (I), for example,those incorporating a radioactive isotope, are useful in drug and/orsubstrate tissue distribution studies. The radioactive isotopes tritium,i.e. ³H, and carbon-14, i.e. ¹⁴C, are particularly useful for thispurpose in view of their ease of incorporation and ready means ofdetection.

Substitution with heavier isotopes such as deuterium, i.e. ²H, mayafford certain therapeutic advantages resulting from greater metabolicstability, for example, increased in vivo half-life or reduced dosagerequirements, and hence may be preferred in some circumstances.

Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and¹³N, can be useful in Positron Emission Topography (PET) studies forexamining substrate receptor occupancy.

Isotopically-labeled compounds of formula (I) can generally be preparedby conventional techniques known to those skilled in the art or byprocesses analogous to those described in the accompanying Examples andPreparations using appropriate isotopically-labeled reagents in place ofthe non-labeled reagent previously employed.

Additionally, Formula (I) is intended to cover, where applicable,solvated as well as unsolvated forms of the compounds. Thus, eachformula includes compounds having the indicated structure, including thehydrated as well as the non-hydrated forms.

The term “pharmaceutically acceptable salts” refers to salts that retainthe desired biological activity of the above-identified compounds, andinclude pharmaceutically acceptable acid addition salts and baseaddition salts. Suitable pharmaceutically acceptable acid addition saltsof compounds of Formula (I) may be prepared from an inorganic acid orfrom an organic acid. Examples of such inorganic acids are hydrochloric,sulfuric, and phosphoric acid. Appropriate organic acids may be selectedfrom aliphatic, cycloaliphatic, aromatic, heterocyclic carboxylic andsulfonic classes of organic acids, examples of which are formic, acetic,propionic, succinic, glycolic, gluconic, lactic, malic, tartaric,citric, fumaric, maleic, alkyl sulfonic, arylsulfonic. Additionalinformation on pharmaceutically acceptable salts can be found inRemington's Pharmaceutical Sciences, 19th Edition, Mack Publishing Co.,Easton, Pa. 1995. In the case of agents that are solids, it isunderstood by those skilled in the art that the inventive compounds,agents and salts may exist in different crystalline or polymorphicforms, all of which are intended to be within the scope of the presentinvention and specified formulae.

“Prodrug” means a compound that undergoes conversion to a compound offormula (I) within a biological system, usually by metabolic means (e.g.by hydrolysis, reduction or oxidation). For example an ester prodrug ofa compound of formula (I) containing a hydroxyl group may be convertibleby hydrolysis in vivo to the parent molecule. Suitable esters ofcompounds of formula (I) containing a hydroxyl group, are for exampleacetates, citrates, lactates, tartrates, malonates, oxalates,salicylates, propionates, succinates, fumarates, maleates,methylene-bis-β-hydroxynaphthoates, gestisates, isethionates,di-p-toluoyltartrates, methanesulphonates, ethanesulphonates,benzenesulphonates, p-toluenesulphonates, cyclohexylsulphamates andquinates. As another example an ester prodrug of a compound of formula(I) containing a carboxy group may be convertible by hydrolysis in vivoto the parent molecule. (Examples of ester prodrugs are those describedby F. J. Leinweber, Drug Metab. Res., 18:379, 1987). Similarly, an acylprodrug of a compound of formula (I) containing an amino group may beconvertible by hydrolysis in vivo to the parent molecule (Many examplesof prodrugs for these and other functional groups, including amines, aredescribed in Prodrugs: Challenges and Rewards (Parts 1 and 2); Ed V.Stella, R. Borchardt, M. Hageman, R. Oliyai, H. Maag and J Tilley;Springer, 2007)

As with any group of structurally related compounds which possess aparticular utility, certain embodiments of variables of the compounds ofthe Formula (I), are particularly useful in their end use application.

In the compounds of the invention Y is a group of the formula—(CR⁹R¹⁰)_(n)—. In one embodiment of the invention n is 1 and Y is—CR⁹R¹⁰—. In another embodiment of the invention n is 2 and Y is—CR⁹R¹⁰CR⁹R¹⁰—.

In one embodiment of the compounds of the invention each R⁹ and R¹⁰ isindependently selected from H and CH₃. In one specific embodiment R⁹ andR¹⁰ are both H. Accordingly in one embodiment of the invention Y is—CH₂—. In another embodiment of the invention Y is —CH₂CH₂—. In yet aneven further embodiment of the invention Y is —C(CH₃)₂—.

In one embodiment of the compounds of the invention R² is H or C₁-C₆alkyl. In a specific embodiment R² is H.

In one embodiment of the compounds of the invention R³ is H or C₁-C₆alkyl. In a specific embodiment R³ is H.

In one embodiment of the compounds of the invention X is selected fromthe group consisting of —C(═O)— and —(CR¹¹R¹²)_(s)—. In one specificembodiment X is —C(═O)—. In one embodiment of the invention where X is—(CR¹¹R¹²)_(s)—, s is 1. In another embodiment of the invention where Xis —(CR¹¹R¹²)_(s)—, s is 2. In one form of each of these embodiments R¹¹and R¹² are each independently selected from the group consisting of Hand C₁-C₆ alkyl. In a specific embodiment both R¹¹ and R¹² are H, and sis 1, such that X is —CH₂—.

In one embodiment of the compounds of the invention Y is CH₂, R² is H,R³ is H, and X is —C(═O)—. This provides compounds of formula (II).

wherein R¹, R^(4a), R^(4b), R^(5a), R^(5b), R⁶, R⁷, R⁸, Z and r are asdefined for formula (I).

In one embodiment of the compounds of the invention and in particularthe compounds of formula (I) and formula (II) r is selected from thegroup consisting of 1, 2, 3, and 4. In one specific embodiment r is 1.In another specific embodiment r is 2. In yet a further specificembodiment r is 3. In an even further specific embodiment r is 4.

In one embodiment of the compounds of the invention, and in particularthe compounds of formula (I), and formula (II) R^(5a) and R^(5b) areindependently selected from H and C₁-C₆ alkyl. In one embodiment R^(5a)and R^(5b) are each independently selected from H and CH₃. In onespecific embodiment R^(5a) and R^(5b) are both H. In yet anotherembodiment at least one of R^(5a) and R^(5b) when taken together with atleast one of R⁶, R⁷ and R⁸ and the atoms to which they are attached forman optionally substituted cycloalkyl group. In one specific embodimentat least one of R^(5a) and R^(5b) when taken together with at least oneof R⁶, R⁷ and R⁸ and the atoms to which they are attached forms acyclohexyl group.

In one embodiment of the compounds of the invention, Y is CH₂, R² is H,R³ is H, R^(5a) and R^(5b) are H, X is —C(═O)—, and r is 1. Thisprovides compounds of formula (III).

wherein R¹, R^(4a), R^(4b), R⁶, R⁷, R⁸, and Z are as defined for formula(I).

In one embodiment of the compounds of the invention, and specifically ofthe compounds of formula (I), (II) and (III), R⁷ is H.

In one embodiment of the compounds of the invention, Y is CH₂, R² is H,R³ is H, R^(5a) and R^(5b) are H, R⁷ is H, X is —C(═O)—, and r is 1.This provides compounds of formula (IV).

wherein R¹, R^(4a), R^(4b), R⁶, R⁸, and Z are as defined for formula(I).

In the compounds of the invention Z is a group of formula—(CR¹³R¹⁴)_(q)—. In one embodiment of the compounds of the invention,and in particular the compounds of formula (I), formula (II), formula(III) and formula (IV), R¹³ and R¹⁴ are independently selected from Hand C₁-C₆ alkyl. In one embodiment R¹³ and R¹⁴ are each independentlyselected from H and CH₃. In one specific embodiment R¹³ and R¹⁴ are bothH. Accordingly in one specific embodiment Z is a group —(CH₂)_(q)—. Inyet another embodiment at least one of R¹³ and R¹⁴ when taken togetherwith at least one of R^(4a) and R^(4b) and the atoms to which they areattached form an optionally substituted heterocycloalkyl group.

In one embodiment of the compounds of the invention and in particular ofthe compounds of formula (IV), q is an integer selected from the groupconsisting of 0, 1, 2, 3, 4, and 5. In one specific embodiment q is 1.In another specific embodiment q is 2, in yet an even further specificembodiment q is 3, and in yet an even further specific embodiment q is4. In circumstances where R¹³ and R¹⁴ are both H this provides compoundsof formula (IVa), (IVb), (IVc) and (IVd) respectively.

wherein R¹, R^(4a), R^(4b), R⁶, and R⁸ are as defined for formula (I).

wherein R¹, R^(4a), R^(4b), R⁶, and R⁸ are as defined for formula (I).

wherein R¹, R^(4a), R^(4b), R⁶, and R⁸ are as defined for formula (I).

wherein R¹, R^(4a), R^(4b), R⁶, and R⁸ are as defined for formula (I).

In one embodiment of the invention, and specifically of the compounds offormula (I), (II) (III), (IV), (IVa), (IVb), (IVc), and (IVd), R⁶ and R⁸are each independently selected from the group consisting of H,optionally substituted C₁-C₁₂ alkyl, optionally substituted C₂-C₁₂alkenyl, optionally substituted C₆-C₁₈ aryl and optionally substitutedC₁-C₁₈heteroaryl.

In one embodiment of the invention, and specifically of the compounds offormula (I), (II) (III), (IV), (IVa), (IVb), (IVc), and (IVd), R⁶ and R⁸are each independently selected from the group consisting of optionallysubstituted C₁-C₁₂ alkyl, optionally substituted C₂-C₁₂ alkenyl,optionally substituted C₆-C₁₈ aryl and optionally substitutedC₁-C₁₈heteroaryl.

In one embodiment of the invention, and specifically of the compounds offormula (I), (II) (III), (IV), (IVa), (IVb), (IVc), and (IVd), R⁶ and R⁸are each independently selected from the group consisting of optionallysubstituted C₂-C₁₂ alkyl, optionally substituted C₂-C₁₂ alkenyl,optionally substituted C₆-C₁₈ aryl and optionally substitutedC₁-C₁₈heteroaryl.

In one specific embodiment of the compounds of the invention, andspecifically of the compounds of formula (I), (II) (III), (IV), (IVa),(IVb), (IVc), and (IVd), R⁶ is selected from the group consisting ofethyl, 2,2,2-trifluoroethyl, isopropyl, isopropenyl, propyl,2-ethyl-propyl, 3,3-dimethyl-propyl, butyl, 2-methyl-butyl, isobutyl,3,3-dimethyl-butyl, 2-ethyl-butyl, pentyl, 2-methyl-pentyl, optionallysubstituted phenyl and optionally substituted C₁-C₅ heteroaryl.

In one specific embodiment of the compounds of the invention andspecifically of the compounds of formula (I), (II) (III), (IV), (IVa),(IVb), (IVc), and (IVd), R⁶ is optionally substituted phenyl oroptionally substituted C₁-C₁₈heteroaryl.

In one embodiment of the compounds of the invention and specifically ofthe compounds of formula (I), (II) (III), (IV), (IVa), (IVb), (IVc), and(IVd), R⁸ is selected from the group consisting of ethyl,2,2,2-trifluoroethyl, isopropyl, isopropenyl, propyl, 2-ethyl-propyl,3,3-dimethyl-propyl, butyl, 2-methyl-butyl, isobutyl,3,3-dimethyl-butyl, 2-ethyl-butyl, pentyl, 2-methyl-pentyl, optionallysubstituted phenyl and optionally substituted C₁-C₅ heteroaryl.

In one specific embodiment of the compounds of the invention andspecifically of the compounds of formula (I), (II) (III), (IV), (IVa),(IVb), (IVc), and (IVd), R⁸ is methyl, ethyl, phenyl or optionallysubstituted C₁-C₅ heteroaryl.

In one specific embodiment of the compounds of the invention andspecifically of the compounds of formula (I), (II) (III), (IV), (IVa),(IVb), (IVc), and (IVd), R⁶, R⁷ and R⁸ when taken together with thecarbon atom to which they are attached form a moiety selected from thegroup consisting of optionally substituted C₂-C₁₂alkenyl, optionallysubstituted C₃-C₁₂cycloalkyl, optionally substitutedC₂-C₁₂heterocycloalkyl, optionally substituted C₆-C₁₈aryl, andoptionally substituted C₁-C₁₈heteroaryl.

In one specific embodiment of the compounds of the invention andspecifically of the compounds of formula (I), (II) (III), (IV), (IVa),(IVb), (IVc), and (IVd), R⁶, R⁷ and R⁸ when taken together with thecarbon atom to which they are attached form an optionally substitutedC₆-C₁₈aryl group.

In one specific embodiment of the compounds of the invention andspecifically of the compounds of formula (I), (II) (III), (IV), (IVa),(IVb), (IVc), and (IVd), R⁶, R⁷ and R⁸ when taken together with thecarbon atom to which they are attached form a disubstituted phenylgroup. In one embodiment the disubstituted phenyl group is a2,4-disubstituted phen-1-yl group or a 3,5-disubstituted phen-1-ylgroup. A wide variety of substituents may be present on thedisubstituted phenyl group as defined above. Examples of particularlysuitable substituents include, but are not limited to, F, Br, Cl,methyl, trifluoromethyl, ethyl, 2,2,2-trifluoroethyl, isopropyl, propyl,2-ethyl-propyl, 3,3-dimethyl-propyl, butyl, isobutyl,3,3-dimethyl-butyl, 2-ethyl-butyl, pentyl, 2-methyl-pentyl, pent-4-enyl,hexyl, heptyl, octyl, phenyl, NH₂, cyano, phenoxy, hydroxy, methoxy,ethoxy, methylenedioxy, pyrrol-1-yl, and 3,5-dimethyl-pyrazol-1-yl. Inone specific embodiment the disubstituted phenyl group is a3,5-dichlorophen-1-yl group.

In one embodiment of the compounds of the invention, and specifically ofthe compounds of formula (IV), (IVa, (IVb), (IVc) and (IVd), R^(4a) isselected from the group consisting of H, C(═NH)NH₂, C(═NH)N(CH₃)₂,C(═NH)NHCH₃, C(═NH)NHisopropyl, C(═O)CH₃, C(═O)cyclohexyl, CH₃, CH₂CH₃,CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₂CH₃, CH(CH₃)CH₂CH₃, CH₂CH(CH₃)₂, C(CH₃)₃,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, and phenyl, ora halogenated derivative thereof.

In one embodiment of the compounds of the invention and specifically ofthe compounds of formula (IV), (IVa), (IVb), (IVc) and (IVd), R^(4b) isselected from the group consisting of H, CH₃, CH₂CH₃, CH₂CH₂CH₃,CH(CH₃)₂, CH₂CH₂CH₂CH₃, CH(CH₃)CH₂CH₃, CH₂CH(CH₃)₂, C(CH₃)₃,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, and phenyl, ora halogenated derivative thereof.

In one embodiment of the compounds of the invention and specifically ofthe compounds of formula (IV), (IVa), (IVb), (IVc) and (IVd), R^(4a) andR^(4b) when taken together with the nitrogen atom to which they areattached form an optionally substituted cyclic group. The optionallysubstituted cyclic group may be an optionally substitutedC₂-C₁₂heterocycloalkyl group, an optionally substituted C₁-C₁₂heterocycloalkenyl group or an optionally substituted C₁-C₁₈ heteroarylgroup. In one specific embodiment R^(4a) and R^(4b) when taken togetherwith the nitrogen atom to which they are attached form an optionallysubstituted C₂-C₁₂heterocycloalkyl group.

In one embodiment of the invention, and specifically of the compounds offormula (IV), (IVa), (IVb), (IVc) and (IVd), R^(4a) and R^(4b) whentaken together with the nitrogen atom to which they are attached form anoptionally substituted heterocycloalkyl group selected from the groupconsisting of piperidin-1-yl, pyrrolidin-1-yl, morpholin-4-yl,piperazin-1-yl and azepan-1-yl.

Specific examples of NR^(4a)R^(4b) include:

In one embodiment of the invention, and specifically of the compounds offormula (IV) one of R^(4a) and R^(4b) when taken together with thenitrogen atom to which it is attached and one of R¹³ and R¹⁴ and thecarbon atom to which it is attached form an optionally substitutedC₂-C₁₂heterocycloalkyl group.

In one embodiment of the invention, and specifically of the compounds offormula (IV), one of R^(4a) and R^(4b) when taken together with thenitrogen atom to which it is attached and one of R¹³ and R¹⁴ and thecarbon atom to which it is attached form an optionally substitutedC₂-C₁₂heterocycloalkyl group selected from the group consisting ofpiperidinyl, pyrrolidinyl, azetidinyl, morpholinyl, piperazinyl, and1-azepanyl.

Specific examples of such a side chain ZN(R^(4a))(R^(4b)) wherein thereis cyclisation between one or R^(4a) and R^(4b) and one of R¹³ and R¹⁴include:

In one embodiment of the compounds of the invention and specifically ofthe compounds of formula (I), (II) (III), (IV), (IVa), (IVb), (IVc), and(IVd), R¹ is selected from the group consisting of optionallysubstituted C₂-C₁₂alkenyl, optionally substituted C₆-C₁₈aryl andoptionally substituted C₁-C₁₈heteroaryl.

In one embodiment of the compounds of the invention and specifically ofthe compounds of formula (I), (II) (III), (IV), (IVa), (IVb), (IVc), and(IVd), R¹ is optionally substituted C₆-C₁₈aryl. The C₆-C₁₈aryl may be amonocyclic, bicyclic or polycyclic moiety. In certain embodiments theC₆-C₁₈aryl is a monocyclic moiety. In certain embodiments the C₆-C₁₈arylis a bicyclic moiety.

In one specific embodiment R¹ is an optionally substituted C₆-C₁₈arylselected from the group consisting of optionally substituted phenyl,biphenyl, and optionally substituted naphthyl. The moieties may beunsubstituted or may be substituted with one or more optionalsubstituents. A wide variety of optional substituents may be used asdefined above. Examples of particularly suitable optional substituentsinclude, but are not limited to, F, Br, Cl, methyl, trifluoromethyl,ethyl, 2,2,2-trifluoroethyl, isopropyl, propyl, 2-ethyl-propyl,3,3-dimethyl-propyl, butyl, isobutyl, 3,3-dimethyl-butyl, 2-ethyl-butyl,pentyl, 2-methyl-pentyl, pent-4-enyl, hexyl, heptyl, octyl, phenyl, NH₂,cyano, phenoxy, hydroxy, methoxy, ethoxy, pyrrol-1-yl, and3,5-dimethyl-pyrazol-1-yl.

The substituents may be located at any substitutable position around thearyl ring available for substitution as would be clear to a skilledaddressee. Examples of suitable optionally substituted phenyl compoundsinclude, but are not limited to, 2-methoxy-phenyl, 3-methoxy-phenyl,4-methoxy-phenyl, 2-trifluoromethyl-phenyl, 3-trifluoromethyl-phenyl,4-trifluoromethyl-phenyl, 2-chloro-phenyl, 3-chloro-phenyl,4-chloro-phenyl, 4-bromo-phenyl, 2-fluoro-phenyl, 3-fluoro-phenyl,4-fluoro-phenyl, 4-hydroxy-phenyl, 4-phenyl-phenyl, 4-methyl-phenyl,2,4-dichloro-phenyl, 3,4-dichloro-phenyl, 2,5-dichloro-phenyl,2,6-difluoro-phenyl, 2-chloro-6-fluoro-phenyl, 3-fluoro-4-chloro-phenyl,3-methyl-4-chloro-phenyl, 3-chloro-4-fluoro-phenyl,3-chloro-4-methyl-phenyl, 2-hydroxy-phenyl, 3-hydroxy-phenyl,4-hydroxy-phenyl, 4-ethoxy-phenyl, 3-phenoxy-phenyl, 4-phenoxy-phenyl,2-methyl-phenyl, 3-methyl-phenyl, 4-methyl-phenyl, 4-isopropyl-phenyl,4-cyano-phenyl, 3,4-dimethyl-phenyl, 2,4-dimethyl-phenyl,4-t-butyl-phenyl, 2,4-dimethoxy-phenyl, and 3,4-methylenedioxy-phenyl.

When R¹ is optionally substituted biphenyl the point of attachment of R¹to the remainder of the molecule may be at the 2-, 3- or 4-positionrelative to the point of attachment of the second phenyl ring. As suchthe biphenyl may be an optionally substituted biphen-2-yl, or anoptionally substituted biphen-3-yl, or an optionally substitutedbiphen-4-yl. In general the optionally substituted biphenyl is anoptionally substituted biphen-4-yl. The optionally substituted biphenylmay be substituted in any suitable position.

When R¹ is optionally substituted naphthyl the point of attachment of R¹to the remainder of the molecule may be at the 1 or 2 positions. As suchthe naphthyl may be an optionally substituted naphth-1-yl, or anoptionally substituted naphth-2-yl. In general the optionallysubstituted naphthyl is an optionally substituted naphth-2-yl. Theoptionally substituted naphthyl may be substituted in any suitableposition. Examples of suitable optionally substituted naphth-2-ylsinclude, but are not limited to, 6-fluoro-naphth-2-yl,6-bromo-naphth-2-yl, 6-chloro-naphth-2-yl, 1-methoxy-naphth-2-yl,3-methoxy-naphth-2-yl, 6-methoxy-naphth-2-yl, 1-hydroxy-naphth-2-yl, and6-amino-naphth-2-yl.

In one embodiment of the compounds of the invention and specifically ofthe compounds of formula (I), (II) (III), (IV), (IVa), (IVb), (IVc), and(IVd), R¹ is optionally substituted C₁-C₁₈heteroaryl. TheC₁-C₁₈heteroaryl may be a monocyclic, bicyclic or polycyclic moiety. Incertain embodiments the C₁-C₁₈heteroaryl is a monocyclic moiety. Incertain embodiments the C₁-C₁₈heteroaryl is a bicyclic moiety. Examplesof suitable heteroaryl moieties include, but are not limited to,indol-2-yl, indol-3-yl quinolin-2-yl quinolin-3-yl, isoquinolin-3-yl,quinoxaline-2-yl, benzo[b]furan-2-yl, benzo[b]thiophen-2-yl,benzo[b]thiophen-5-yl, thiazole-4-yl, benzimidazole-5-yl,benzotriazol-5-yl, furan-2-yl, benzo[d]thiazole-6-yl, pyrazole-1-yl,pyrazole-4-yl and thiophen-2-yl. These may also be optionallysubstituted as discussed above.

In one embodiment of the compounds of the invention and specifically ofthe compounds of formula (I), (II) (III), (IV), (IVa), (IVb), (IVc), and(IVd), R¹ is an optionally substituted C₂-C₁₂alkenyl. The optionallysubstituted alkenyl may contain one or more double bonds with each ofthe double bonds being independently in the E or Z configuration. In oneembodiment of the invention the alkenyl contains a single double bondwhich is in the E configuration.

In one specific form of this embodiment R¹ is an optionally substitutedC₂-C₁₂alkenyl of the formula:

R^(1a) is selected from the group consisting of H, halogen andoptionally substituted C₁-C₁₂ alkyl;

R^(1b) and R^(1c) are each independently selected from the groupconsisting of H, halogen, optionally substituted C₁-C₁₂alkyl, optionallysubstituted C₂-C₁₂alkenyl, optionally substituted C₂-C₁₂alkynyl,optionally substituted C₁-C₁₂heteroalkyl, optionally substitutedC₃-C₁₂cycloalkyl, optionally substituted C₂-C₁₂ heterocycloalkyl,optionally substituted C₆-C₁₈aryl, and optionally substitutedC₁-C₁₈heteroaryl.

In one form of this embodiment R^(1a) is H. In one form of thisembodiment R^(1b) is H. This provides compounds where R¹ is of theformula:

In one embodiment of the compounds of the invention R^(1c) is optionallysubstituted C₆-C₁₈aryl. The C₆-C₁₈aryl may be monocyclic, bicyclic orpolycyclic moiety. In certain embodiments the C₆-C₁₈aryl is a monocyclicmoiety. In certain embodiments the C₆-C₁₈aryl is a bicyclic moiety.

In one specific embodiment R^(1c) is an optionally substitutedC₆-C₁₈aryl selected from the group consisting of optionally substitutedphenyl and optionally substituted naphthyl. The moieties may beunsubstituted or may be substituted with one or more optionalsubstituents. A wide variety of optional substituents may be used asdefined above. Examples of particularly suitable optional substituentsinclude, but are not limited to, F, Br, Cl, methyl, trifluoromethyl,ethyl, 2,2,2-trifluoroethyl, isopropyl, propyl, 2-ethyl-propyl,3,3-dimethyl-propyl, butyl, isobutyl, 3,3-dimethyl-butyl, 2-ethyl-butyl,pentyl, 2-methyl-pentyl, pent-4-enyl, hexyl, heptyl, octyl, phenyl, NH₂,cyano, phenoxy, hydroxy, methoxy, ethoxy, methylenedioxy, pyrrol-1-yl,and 3,5-dimethyl-pyrazol-1-yl.

The substituents may be located at any substitutable position around thearyl ring available for substitution as would be clears to a skilledaddressee. Examples of suitable optionally substituted phenyl compoundsinclude, but are not limited to, 2-methoxy-phenyl, 3-methoxy-phenyl,4-methoxy-phenyl, 2-trifluoromethyl-phenyl, 3-trifluoromethyl-phenyl4-trifluoromethyl-phenyl 2-chloro-phenyl, 3-chloro-phenyl,4-chloro-phenyl, 4-bromo-phenyl, 2-fluoro-phenyl 3-fluoro-phenyl,4-fluoro-phenyl, 4-hydroxy-phenyl 4-phenyl-phenyl, 4-methyl-phenyl,2,4-dichloro-phenyl, 3,4-dichloro-phenyl, 2,5-dichloro-phenyl,2,6-difluoro-phenyl, 2-chloro-6-fluoro-phenyl, 3-fluoro-4-chloro-phenyl,3-methyl-4-chloro-phenyl, 3-chloro-4-fluoro-phenyl,3-chloro-4-methyl-phenyl, 2-hydroxy-phenyl 3-hydroxy-phenyl4-hydroxy-phenyl, 4-ethoxy-phenyl, 3-phenoxy-phenyl, 4-phenoxy-phenyl,2-methyl-phenyl, 3-methyl-phenyl, 4-methyl-phenyl, 4-isopropyl-phenyl,4-cyano-phenyl 3,4-dimethyl-phenyl, 2,4-dimethyl-phenyl,4-t-butyl-phenyl, 2,4-dimethoxy-phenyl, and 3,4-methylenedioxy-phenyl.

Specific compounds of the invention include the following:

or a pharmaceutically acceptable salt or prodrug thereof.

In order to assist the reader the names of the compounds of theinvention as discussed above are as follows:

-   (14)    N-(((3S,5S)-1-(3,5-dichlorobenzyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (25)    N-(((3S,5S)-3-(2-(diethylamino)ethyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-6-fluoro-2-naphthamide-   (31)    N-(((3S,5S)-3-(2-aminoethyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-6-fluoro-2-naphthamide-   (33)    (E)-3-(4-chlorophenyl)-N-(((3S,5S)-1-(2,2-diphenylethyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)acrylamide-   (37)    N-(((3S,5S)-3-(2-aminoethyl)-2-oxo-1-(2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (38)    N-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (39)    N-(((3S,5S)-2-oxo-1-((R)-2-phenylbutyl)-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (49)    N-(((3S,5S)-3-(2-aminoethyl)-1-(3,5-dichlorobenzyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (50)    N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)naphthalene-2-sulfonamide-   (54)    N-(((3S,5S)-3-(2-aminoethyl)-1-(2-ethylbutyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (60)    N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-6-bromo-N-methyl-2-naphthamide-   (62)    N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylethyl)-4-methyl-2-oxo-1,4-diazepan-5-yl)methyl)-6-bromo-2-naphthamide-   (63)    N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (64)    N-(((3S,5S)-1-(2,2-diphenylethyl)-2-oxo-3-(3-(piperidin-1-yl)propyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (65)    N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-(isopropylamino)propyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (67)    N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-(3-methylguanidino)propyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (71)    (E)-N-(((3S,5S)-3-butyl-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(4-chlorophenyl)acrylamide-   (79)    N—((S)-1-((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)-2-(naphthalen-2-yl)ethyl)acetamide-   (81)    (S)-2-acetamido-N—((S)-1-((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)-2-(naphthalen-2-yl)ethyl)-3-(1H-imidazol-5-yl)propanamide-   (83) propyl    (S)-1-((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)-2-(naphthalen-2-yl)ethylcarbamate-   (85)    N—((R)-1-((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)-2-(naphthalen-2-yl)ethyl)acetamide-   (86)    (S)-2-acetamido-N—((R)-1-((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)-2-(naphthalen-2-yl)ethyl)-3-(1H-imidazol-4-yl)propanamide-   (87) propyl    (R)-1-((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)-2-(naphthalen-2-yl)ethylcarbamate-   (105)    N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (106)    N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)biphenyl-4-carboxamide-   (107)    N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-1H-indole-2-carboxamide-   (108)    N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)biphenyl-4-carboxamide-   (109)    N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-1H-indole-2-carboxamide-   (110)    N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-(naphthalen-2-yl)acetamide-   (111)    N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-1,2,3,4-tetrahydronaphthalene-2-carboxamide-   (112)    N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)quinoline-3-carboxamide-   (113)    N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)quinoxaline-2-carboxamide-   (114)    N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)isoquinoline-3-carboxamide-   (115)    N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)benzamide-   (116)    N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)quinoline-2-carboxamide-   (117)    N-(((3S,5S)-3-(4-aminobutyl)-1-(naphthalen-1-ylmethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (118)    N-(((3S,5S)-3-(4-aminobutyl)-1-(naphthalen-1-ylmethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-(naphthalen-2-yl)acetamide-   (119)    N-(((3S,5S)-3-(4-aminobutyl)-1-(naphthalen-1-ylmethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-1-naphthamide-   (120)    N-(((3S,5S)-3-(4-aminobutyl)-1-(naphthalen-1-ylmethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-(1H-indol-3-yl)acetamide-   (121)    N-(((3S,5S)-3-(4-aminobutyl)-1-(naphthalen-2-ylmethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-(biphenyl-4-yl)acetamide-   (122)    N-(((3S,5S)-3-(4-aminobutyl)-1-(naphthalen-2-ylmethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (123)    N-(((3S,5S)-3-(4-aminobutyl)-1-(naphthalen-2-ylmethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-(naphthalen-2-yl)acetamide-   (124)    N-(((3S,5S)-3-(4-aminobutyl)-1-(naphthalen-2-ylmethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-1-naphthamide-   (125)    N-(((3S,5S)-3-(4-aminobutyl)-1-(naphthalen-2-ylmethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-(naphthalen-1-yl)acetamide-   (126)    N-(((3S,5S)-3-(4-aminobutyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (127)    (S)—N-(((3S,5S)-3-(4-aminobutyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide-   (128)    (R)—N-(((3S,5S)-3-(4-aminobutyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide-   (129)    N-(((3S,5S)-3-(4-aminobutyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)benzofuran-2-carboxamide-   (130)    (R)—N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-(3-methylguanidino)propyl)-2-oxo-1,4-diazepan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide-   (131)    (S)—N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide-   (132)    N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)benzofuran-2-carboxamide-   (133)    N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2,3-dihydro-1H-indene-2-carboxamide-   (134)    (R)—N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide-   (135)    N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)benzo[b]thiophene-2-carboxamide-   (136)    2,4-dichloro-N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)benzamide-   (137)    2,5-dichloro-N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)benzamide-   (138)    N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)benzamide-   (139)    N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)cyclohexanecarboxamide-   (140)    N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-phenoxybenzamide-   (141)    N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-4-phenoxybenzamide-   (142)    N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-1H-indole-2-carboxamide-   (143)    N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-phenylpropanamide-   (144)    N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3,4-dimethylbenzamide-   (145)    4-tert-butyl-N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)benzamide-   (146)    N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2,4-dimethoxybenzamide-   (147)    2-cyclohexyl-N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)acetamide-   (148)    N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide-   (149)    N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-1H-benzo[d]imidazole-5-carboxamide-   (150)    N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-1H-benzo[d][1,2,3]triazole-5-carboxamide-   (151)    N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)cyclopentanecarboxamide-   (152)    3,4-dichloro-N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)benzamide-   (153)    N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)cinnamamide-   (154)    3,5-dichloro-N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)benzamide-   (155)    2-(2,4-dichlorophenyl)-N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)acetamide-   (156)    N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-1-methoxy-2-naphthamide-   (157)    2-(3,4-dichlorophenyl)-N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)acetamide-   (158)    N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-6-methoxy-2-naphthamide-   (159)    (E)-3-(2,4-dichlorophenyl)-N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)acrylamide-   (160)    N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-adamantane-1-carboxamide-   (161)    N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-phenoxyacetamide-   (162)    N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-methoxy-2-naphthamide-   (163)    4-bromo-N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)benzamide-   (164)    (S)—N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2,3-dihydrobenzo[b][1,4]dioxine-2-carboxamide-   (165)    (E)-3-(4-chlorophenyl)-N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)acrylamide-   (166)    (E)-N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(thiophen-2-yl)acrylamide-   (167)    (R)—N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2,3-dihydrobenzo[b][1,4]dioxine-2-carboxamide-   (168)    (E)-N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(4-hydroxyphenyl)acrylamide-   (169)    (E)-N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(2-methoxyphenyl)acrylamide-   (170)    (E)-N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-p-tolylacrylamide-   (171)    (E)-N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(2-(trifluoromethyl)phenyl)acrylamide-   (172)    (E)-N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(3-fluorophenyl)acrylamide-   (173)    (E)-N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-methyl-3-phenylacrylamide-   (174)    N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-phenylcyclopropanecarboxamide-   (175)    2-(2,4-dichlorophenoxy)-N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)acetamide-   (176)    (E)-3-(3-chlorophenyl)-N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)acrylamide-   (177)    N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)benzo[d]thiazole-6-carboxamide-   (178)    N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-5-phenylfuran-2-carboxamide-   (179)    (E)-N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(3-methoxyphenyl)acrylamide-   (180)    6-bromo-N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (181)    N-(((3S,5S)-3-(3-guanidinopropyl)-2-oxo-1-phenethyl-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (182)    N-(((3S,5S)-1-(3,4-dichlorophenethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (183)    N-(((3S,5S)-1-(2,4-dichlorophenethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (184)    N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)benzo[b]thiophene-5-carboxamide-   (185)    N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-5-methyl-1-phenyl-1H-pyrazole-4-carboxamide-   (186)    (E)-N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(4-methoxyphenyl)acrylamide-   (187)    N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-6-fluoro-2-naphthamide-   (188)    (E)-3-(2-chlorophenyl)-N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)acrylamide-   (189)    (E)-N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(2-hydroxyphenyl)acrylamide-   (190)    (E)-N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-m-tolylacrylamide-   (191)    (E)-N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(3-(trifluoromethyl)phenyl)acrylamide-   (192)    (E)-N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(3-hydroxyphenyl)acrylamide-   (193)    (E)-N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(2-fluorophenyl)acrylamide-   (194)    (E)-N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-o-tolylacrylamide-   (195)    (Z)—N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-fluoro-3-phenylacrylamide-   (196)    N-((1-(2,2-diphenylethyl)-2-oxo-3-(piperidin-4-yl)-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (197)    N-((1-(2,2-diphenylethyl)-2-oxo-3-(piperidin-4-ylmethyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (198)    (E)-N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(4-fluorophenyl)acrylamide-   (199)    (E)-N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(4-(trifluoromethyl)phenyl)acrylamide-   (200)    N-(((3S,5S)-1-(2,2-diphenylpropyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (201)    N-(((3S,5S)-1-(cyclohexylmethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (202)    N-(((3S,5S)-1-(1-adamantylmethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (203)    N-(((3S,5S)-1-((S)-1,1-diphenylpropan-2-yl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (204)    N-(((3S,5S)-1-((R)-1,1-diphenylpropan-2-yl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (205)    N-(((3S,5S)-1-cyclohexyl-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (206)    N-(((3S,5S)-1-((R)-1-fluoro-1,1-diphenylpropan-2-yl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (207)    (E)-3-(2,6-difluorophenyl)-N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)acrylamide-   (208)    (E)-3-(2-chloro-6-fluorophenyl)-N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)acrylamide-   (209)    (E)-3-(4-bromophenyl)-N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)acrylamide-   (210)    (E)-N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(4-ethoxyphenyl)acrylamide-   (211)    N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-6-bromo-2-naphthamide-   (212)    N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)cinnamamide-   (213)    (E)-N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(4-chlorophenyl)acrylamide-   (214)    N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-1,4-dimethoxy-2-naphthamide-   (215)    N-(((3S,5S)-3-(3-(3,3-dimethylguanidino)propyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (216)    N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-6-hydroxy-2-naphthamide-   (217)    6-amino-N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (218)    (E)-N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-p-tolylacrylamide-   (219)    (E)-N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(4-fluorophenyl)acrylamide-   (220)    N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-6-fluoro-2-naphthamide-   (221)    N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-ethylhexanamide-   (222)    N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3,4-dimethylbenzamide-   (223)    N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3,4-dichlorobenzamide-   (224)    N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-ethylhexanamide-   (225)    N-(((3S,5S)-3-(3-(cyclohexylamino)propyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (226)    N-(((3S,5S)-3-(3-guanidinopropyl)-1-(naphthalen-2-yl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (227)    N-(((3S,5S)-1-((9H-fluoren-9-yl)methyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (228)    (E)-N-(((3S,5S)-3-(3-(cyclohexylamino)propyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(4-fluorophenyl)acrylamide-   (229)    N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(4-(isopropylamino)butyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (230)    (E)-N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(2,4-difluorophenyl)acrylamide-   (231)    (E)-N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(4-cyanophenyl)acrylamide-   (232)    (E)-N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(naphthalen-2-yl)acrylamide-   (233)    N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-(4-fluorophenoxy)acetamide-   (234)    N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-5-(4-chlorophenyl)furan-2-carboxamide-   (235)    N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-4-(1H-pyrrol-1-yl)benzamide-   (236)    N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-oxo-1-phenylpyrrolidine-3-carboxamide-   (237)    N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-5-(4-chlorophenyl)isoxazole-3-carboxamide-   (238)    N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-5-(furan-2-yl)isoxazole-3-carboxamide-   (239)    N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-phenylthiazole-4-carboxamide-   (240)    N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-4-(3,5-dimethyl-1H-pyrazol-1-yl)benzamide-   (241)    N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-5-methyl-1-phenyl-1H-pyrazole-4-carboxamide-   (242)    N-(((3S,5S)-1-(2-cyclohexylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (243)    N-(((3S,5S)-1-(2-(bicyclo[2.2.1]heptan-2-yl)ethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (244)    N-(((3S,5S)-1-(2,2-bis(4-methoxyphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (245)    N-(((3S,5S)-3-(3-(benzylamino)propyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (246)    N-(((3S,5S)-3-(3-(cyclopentylamino)propyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (247)    N-(((3S,5S)-3-(3-(cyclobutylamino)propyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (248)    N-(((3S,5S)-3-(3-(dicyclobutylamino)propyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (249)    N-(((3S,5S)-1-benzyl-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (250)    N-(((3S,5S)-1-(2,2-bis(4-fluorophenyl)ethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (251)    N-(((3S,5S)-3-(3-guanidinopropyl)-1-(naphthalen-2-yl)methyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (252)    (E)-N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(5-methylthiophen-2-yl)acrylamide-   (253)    N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-phenyl-1H-pyrazole-5-carboxamide-   (254)    (E)-N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(4-fluorophenyl)-N-methylacrylamide-   (255)    (E)-N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylethyl)-4-methyl-2-oxo-1,4-diazepan-5-yl)methyl)-3-(4-fluorophenyl)acrylamide-   (256)    N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-4-(3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl)benzamide-   (257)    (E)-N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(4-bromophenyl)acrylamide-   (258)    (E)-3-(4-chlorophenyl)-N-(((3S,5S)-1-(2,2-diphenylethyl)-2-oxo-3-(3-(pyrrolidin-1-yl)propyl)-1,4-diazepan-5-yl)methyl)acrylamide-   (259)    (E)-3-(4-chlorophenyl)-N-(((3S,5S)-1-(2,2-diphenylethyl)-2-oxo-3-(3-(piperidin-1-yl)propyl)-1,4-diazepan-5-yl)methyl)acrylamide-   (260)    N-(((3S,5S)-3-(2-aminoethyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (261)    N-(((3S,5S)-1-(2,2-diphenylethyl)-2-oxo-3-(3-(pyrrolidin-1-yl)propyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (262)    N-(((3S,5S)-3-(3-(azetidin-1-yl)propyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (263)    N-(((3S,5S)-3-(3-guanidinopropyl)-1-(naphthalen-1-ylmethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (264)    N-(((3S,5S)-3-(3-guanidinopropyl)-1-(2-(naphthalen-2-yl)ethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (265)    N-(((3S,5S)-1-((S)-2-acetamido-2-phenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (266)    N-(((3S,5S)-1-(2,2-diphenylethyl)-2-oxo-3-(3-(piperidin-1-yl)propyl)-1,4-diazepan-5-yl)methyl)cinnamamide-   (267)    N-(((3S,5S)-1-(2,2-diphenylethyl)-2-oxo-3-(3-(piperidin-1-yl)propyl)-1,4-diazepan-5-yl)methyl)-3,4-dimethylbenzamide-   (268)    3,4-dichloro-N-(((3S,5S)-1-(2,2-diphenylethyl)-2-oxo-3-(3-(piperidin-1-yl)propyl)-1,4-diazepan-5-yl)methyl)benzamide-   (269)    N-(((3S,5S)-1-((S)-2-(cyclobutanecarboxamido)-2-phenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (270)    N-(((3S,5S)-1-((S)-2-(cyclohexanecarboxamido)-2-phenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (271)    N-(((3S,5S)-3-(aminomethyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (272)    (E)-N-(((3S,5S)-3-(aminomethyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(4-chlorophenyl)acrylamide-   (273)    (E)-N-(((3S,5S)-3-(2-aminoethyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(4-fluorophenyl)acrylamide-   (274)    (E)-N-(((3S,5S)-3-(2-aminoethyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-p-tolylacrylamide-   (275)    N-(((3S,5S)-1-(2,2-diphenylethyl)-2-oxo-3-(piperidin-1-ylmethyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (276)    (E)-3-(4-chlorophenyl)-N-(((3S,5S)-1-(2,2-diphenylethyl)-2-oxo-3-(piperidin-1-ylmethyl)-1,4-diazepan-5-yl)methyl)acrylamide-   (277)    N-(((3S,5S)-3-(2-aminoethyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3,4-dichlorobenzamide-   (278)    N-(((3S,5S)-3-(2-aminoethyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3,4-dimethylbenzamide-   (279)    N-(((3S,5S)-3-(2-aminoethyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)cinnamamide-   (280)    (E)-N-(((3S,5S)-3-(2-aminoethyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(4-chlorophenyl)acrylamide-   (281)    3,4-dichloro-N-(((3S,5S)-1-(2,2-diphenylethyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)benzamide-   (282)    N-(((3S,5S)-1-(2,2-diphenylethyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-3,4-dimethylbenzamide-   (283)    N-(((3S,5S)-1-(2,2-diphenylethyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)cinnamamide-   (284)    (E)-N-(((3S,5S)-1-(2,2-diphenylethyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-3-(4-fluorophenyl)acrylamide-   (285)    (E)-N-(((3S,5S)-1-(2,2-diphenylethyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-3-p-tolylacrylamide-   (286)    N-(((3S,5S)-1-(3,5-dimethylbenzyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (287)    N-(((3S,5S)-1-((S)-2-benzamido-2-phenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (288)    N-(((3S,5S)-1-((R)-2-benzamido-2-phenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (289)    N-(((3S,5S)-3-(3-guanidinopropyl)-1-(2-methoxy-2-phenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (290)    N-(((3S,5S)-3-(3-guanidinopropyl)-2-oxo-1-(2-phenyl-2-propoxyethyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (291)    N-(((3S,5S)-1-(2-(benzyloxy)-2-phenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (292)    N-(((3S,5S)-1-(2-(allyloxy)-2-phenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (293)    (E)-N-(((3S,5S)-3-(3-acetamidopropyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-p-tolylacrylamide-   (294)    N-(3-((2S,7S)-4-(2,2-diphenylethyl)-3-oxo-7-(((E)-3-p-tolylacrylamido)methyl)-1,4-diazepan-2-yl)propyl)cyclohexanecarboxamide-   (295)    N-(((3S,5S)-3-(3-guanidinopropyl)-2-oxo-1-(2-phenoxy-2-phenylethyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (296) ethyl    3-((3S,5S)-5-((2-naphthamido)methyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-1-yl)-2-phenylpropanoate-   (297)    N-(((3S,5S)-1-(2-ethylbutyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (298)    N-(((3S,5S)-1-((3,5-dimethylcyclohexyl)methyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (299)    N-(2-((2S,7S)-7-(((E)-3-(4-chlorophenyl)acrylamido)methyl)-4-(2,2-diphenylethyl)-3-oxo-1,4-diazepan-2-yl)ethyl)cyclohexanecarboxamide-   (300)    (E)-3-(4-chlorophenyl)-N-(((3S,5S)-3-(2-(2-cyclohexylacetamido)ethyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)acrylamide-   (301)    N-(2-((3S,5R)-1-(2,2-diphenylethyl)-2-oxo-3-(2-aminoethyl)-1,4-diazepan-5-yl)ethyl)benzamide-   (302)    3,4-dichloro-N-(2-((3S,5R)-1-(2,2-diphenylethyl)-2-oxo-3-(2-aminoethyl)-1,4-diazepan-5-yl)ethyl)benzamide-   (303)    N-(2-((3S,5R)-1-(2,2-diphenylethyl)-2-oxo-3-(2-aminoethyl)-1,4-diazepan-5-yl)ethyl)-2-naphthamide-   (304)    N-(2-((3S,5R)-1-(2,2-diphenylethyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)ethyl)benzamide-   (305)    3,4-dichloro-N-(2-((3S,5R)-1-(2,2-diphenylethyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)ethyl)benzamide-   (306)    N-(2-((3S,5R)-1-(2,2-diphenylethyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)ethyl)-2-naphthamide-   (307)    N-(((3S,5S)-1-(3-(dimethylamino)-3-oxo-2-phenylpropyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (308)    N-(((3S,5S)-3-(2-aminoethyl)-1-(3,5-dichlorobenzyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3,4-dichlorobenzamide-   (309)    (E)-N-(((3S,5S)-3-(2-aminoethyl)-1-(3,5-dichlorobenzyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(4-chlorophenyl)acrylamide-   (310)    N-(((3S,5S)-1-(3-chloro-5-fluorobenzyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (311)    N-(((3S,5S)-1-(3,5-difluorobenzyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (312)    N-(((3S,5S)-3-(3-aminopropyl)-1-(3-chloro-5-fluorobenzyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (313)    N-(((3S,5S)-3-(3-aminopropyl)-1-(3,5-difluorobenzyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (314)    N-(((3S,5S)-3-(3-aminopropyl)-1-(2,5-dichlorobenzyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (315)    N-(((3S,5S)-3-(3-aminopropyl)-1-(2,6-dichlorobenzyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (316)    N-(((3S,5S)-3-(3-aminopropyl)-1-(3,5-dimethoxybenzyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (317)    N-(((3S,5S)-3-(3-aminopropyl)-1-(2-chlorobenzyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (318)    N-(((3S,5S)-3-(3-aminopropyl)-1-(2,3-dichlorobenzyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (319)    N-(((3S,5S)-3-(3-aminopropyl)-1-(2,4-dichlorobenzyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (320)    N-(((3S,5S)-3-(3-aminopropyl)-1-(3,4-dichlorobenzyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (321)    N-(((3S,5S)-3-(3-aminopropyl)-1-(3-fluoro-5-methylbenzyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (322)    N-(((3S,5S)-3-(3-aminopropyl)-1-(3-fluoro-5-(trifluoromethyl)benzyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (323)    N-(((3S,5S)-3-(3-aminopropyl)-1-(4-chlorobenzyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (324)    N-(((3S,5S)-3-(3-aminopropyl)-2-oxo-1-(2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (325)    N-(((3S,5S)-3-(3-aminopropyl)-2-oxo-1-((1-phenylcyclohexyl)methyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (326)    3,4-dichloro-N-(((3S,5S)-1-(3,5-dichlorobenzyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)benzamide-   (327)    N-(((3S,5S)-1-(3,5-dichlorobenzyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (328)    (E)-3-(4-chlorophenyl)-N-(((3S,5S)-1-(3,5-dichlorobenzyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)acrylamide-   (329)    N-(((3S,5S)-3-(2-aminoethyl)-1-(2-ethylbutyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3,4-dichlorobenzamide-   (330)    (E)-N-(((3S,5S)-3-(2-aminoethyl)-1-(2-ethylbutyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(4-chlorophenyl)acrylamide-   (331)    (E)-3-(4-chlorophenyl)-N-(((3S,5S)-1-(2-ethylbutyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)acrylamide-   (332)    3,4-dichloro-N-(((3S,5S)-1-(2-ethylbutyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)benzamide-   (333)    N-(((3S,5S)-1-(2-ethylbutyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (334)    N-(((3S,5S)-3-(2-aminoethyl)-1-(2-ethylbutyl)-2-oxo-1,4-diazepan-5-yl)methyl)-4-chloro-3-fluorobenzamide-   (335)    N-(((3S,5S)-3-(2-aminoethyl)-1-(2-ethylbutyl)-2-oxo-1,4-diazepan-5-yl)methyl)-4-chloro-3-methylbenzamide-   (336)    N-(((3S,5S)-3-(2-aminoethyl)-1-(2-ethylbutyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-chloro-4-fluorobenzamide-   (337)    N-(((3S,5S)-3-(2-aminoethyl)-1-(2-ethylbutyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-chloro-4-methylbenzamide-   (338)    (E)-3-(4-chlorophenyl)-N-(((3S,5S)-1-(2-ethylbutyl)-2-oxo-3-(piperidin-1-ylmethyl)-1,4-diazepan-5-yl)methyl)acrylamide-   (339)    N-(2-((3S,5R)-1-(2,2-diphenylethyl)-2-oxo-3-(2-(pyrrolidin-1-yl)ethyl)-1,4-diazepan-5-yl)ethyl)-2-naphthamide-   (340)    N-(((3S,5S)-3-(3-aminopropyl)-1-(3,5-bis(trifluoromethyl)benzyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (341)    N-(((3S,5S)-3-(3-aminopropyl)-1-(3-chlorobenzyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (342)    N-(((3S,5S)-2-oxo-1-(2-phenylbutyl)-3-(3-(piperidin-1-yl)propyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (343)    N-(((3S,5S)-3-(3-guanidinopropyl)-2-oxo-1-(3-oxo-2-phenyl-3-(piperidin-1-yl)propyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (344)    N-(((3S,5S)-3-(3-guanidinopropyl)-2-oxo-1-(3-oxo-2-phenyl-3-(phenylamino)propyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (345)    3,4-dichloro-N-(2-((3S,5R)-1-(2,2-diphenylethyl)-3-(2-(isopropylamino)ethyl)-2-oxo-1,4-diazepan-5-yl)ethyl)benzamide-   (346)    3,4-dichloro-N-(2-((3S,5R)-3-(2-(diisopropylamino)ethyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)ethyl)benzamide-   (347)    N-(((3S,5S)-3-(aminomethyl)-1-(3,5-dichlorobenzyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3,4-dichlorobenzamide-   (348)    N-(((3S,5S)-3-(aminomethyl)-1-(3,5-dichlorobenzyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (349)    (E)-N-(((3S,5S)-3-(aminomethyl)-1-(3,5-dichlorobenzyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(4-chlorophenyl)acrylamide-   (350)    3,4-dichloro-N-(((3S,5S)-1-(3,5-dichlorobenzyl)-2-oxo-3-(piperidin-1-ylmethyl)-1,4-diazepan-5-yl)methyl)benzamide-   (351)    (E)-3-(4-chlorophenyl)-N-(((3S,5S)-1-(3,5-dichlorobenzyl)-2-oxo-3-(piperidin-1-ylmethyl)-1,4-diazepan-5-yl)methyl)acrylamide-   (352)    N-(((3S,5S)-3-(2-aminoethyl)-2-oxo-1-(2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-3,4-dichlorobenzamide-   (353)    (E)-N-(((3S,5S)-3-(2-aminoethyl)-2-oxo-1-(2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-3-(4-chlorophenyl)acrylamide-   (354)    3,4-dichloro-N-(((3S,5S)-1-(3,5-dichlorobenzyl)-2-oxo-3-(pyrrolidin-1-ylmethyl)-1,4-diazepan-5-yl)methyl)benzamide-   (355)    N-(((3S,5S)-1-(3,5-dichlorobenzyl)-2-oxo-3-(pyrrolidin-1-ylmethyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (356)    N-(((3S,5S)-3-(3-aminopropyl)-2-oxo-1-((S)-2-phenylpropyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (357)    N-(((3S,5S)-3-(3-aminopropyl)-2-oxo-1-((R)-2-phenylpropyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (358)    N-(((3S,5S)-3-(2-(dimethylamino)ethyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (359)    N-(((3S,5S)-1-(2,2-diphenylethyl)-2-oxo-3-(3-(piperidin-1-yl)propyl)-1,4-diazepan-5-yl)methyl)-6-fluoro-2-naphthamide-   (360)    N-(((3S,5S)-3-(3-aminopropyl)-1-(3,5-diethynylbenzyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (361)    (E)-3-(4-chlorophenyl)-N-(((3S,5S)-3-(2-(diethylamino)ethyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)acrylamide-   (362)    N-(((3S,5S)-3-(2-(diethylamino)ethyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (363)    3,4-dichloro-N-(((3S,5S)-2-oxo-1-((R)-2-phenylbutyl)-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)benzamide-   (364)    (E)-3-(4-chlorophenyl)-N-(((3S,5S)-2-oxo-1-((R)-2-phenylbutyl)-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)acrylamide-   (365)    (E)-3-(4-chlorophenyl)-N-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)acrylamide-   (366)    N-(((3S,5S)-3-(2-aminoethyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-6-chloro-2-naphthamide-   (367)    N-(((3S,5S)-1-(2,2-diphenylethyl)-2-oxo-3-(2-(pyrrolidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (368)    N-(((3S,5S)-1-(2,2-diphenylethyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (369)    N-(((3S,5S)-3-(2-aminoethyl)-1-(2-ethylbutyl)-2-oxo-1,4-diazepan-5-yl)methyl)-6-fluoro-2-naphthamide-   (370)    N-(((3S,5S)-3-(2-aminoethyl)-1-(2-ethylbutyl)-2-oxo-1,4-diazepan-5-yl)methyl)-6-chloro-2-naphthamide-   (371)    N-(((3S,5S)-3-(2-aminoethyl)-1-(2-ethylbutyl)-2-oxo-1,4-diazepan-5-yl)methyl)-6-bromo-2-naphthamide-   (372)    N-(((3S,5S)-1-(2-ethylbutyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-6-fluoro-2-naphthamide-   (373)    6-chloro-N-(((3S,5S)-1-(2-ethylbutyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (374)    6-bromo-N-(((3S,5S)-1-(2-ethylbutyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (375)    N-(((3S,5S)-3-(2-aminoethyl)-1-((3,5-dimethylcyclohexyl)methyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3,4-dichlorobenzamide-   (376)    N-(((3S,5S)-3-(2-aminoethyl)-1-((3,5-dimethylcyclohexyl)methyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (377)    (E)-N-(((3S,5S)-3-(2-aminoethyl)-1-((3,5-dimethylcyclohexyl)methyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(4-chlorophenyl)acrylamide-   (378)    6-chloro-N-(((3S,5S)-1-(2,2-diphenylethyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (379)    N-(((3S,5S)-1-(2,2-diphenylethyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-6-fluoro-2-naphthamide-   (380)    (E)-3-(4-chlorophenyl)-N-(((3S,5S)-1-(2,2-diphenylethyl)-2-oxo-3-(2-(pyrrolidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)acrylamide-   (381)    (E)-3-(4-chlorophenyl)-N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(2-(isopropylamino)ethyl)-2-oxo-1,4-diazepan-5-yl)methyl)acrylamide-   (382)    N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(2-(isopropylamino)ethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (383)    3,4-dichloro-N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(2-(isopropylamino)ethyl)-2-oxo-1,4-diazepan-5-yl)methyl)benzamide-   (384)    N-(((3S,5S)-3-(3-aminopropyl)-1-((2,6-dimethylcyclohexyl)methyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (385)    N-(((3S,5S)-3-(3-aminopropyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (386)    3,4-dichloro-N-(((3S,5S)-1-((3,5-dimethylcyclohexyl)methyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)benzamide-   (387)    3,4-dichloro-N-(((3S,5S)-1-((3,5-dimethylcyclohexyl)methyl)-3-(2-(isopropylamino)ethyl)-2-oxo-1,4-diazepan-5-yl)methyl)benzamide-   (388)    N-(((3S,5S)-3-(2-aminoethyl)-1-(3-methyl-2-phenylbutyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (389)    N-(((3S,5S)-3-(2-aminoethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (390)    N-(((3S,5S)-3-(3-aminopropyl)-2-oxo-1-((R)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (391)    3-(4-chlorophenyl)-N-(((3S,5S)-1-(2,2-diphenylethyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)propanamide-   (392)    N-(((3S,5S)-3-(2-aminoethyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(4-chlorophenyl)propanamide-   (393)    N-(((2S,7S)-7-(((E)-3-(4-chlorophenyl)acrylamido)methyl)-4-(2,2-diphenylethyl)-3-oxo-1,4-diazepan-2-yl)methyl)picolinamide-   (394)    N-(((3S,5S)-1-((R)-3-methyl-2-phenylbutyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (395)    N-(((3S,5S)-1-((S)-3-methyl-2-phenylbutyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (396)    (E)-N-(((3S,5S)-1-(2,2-diphenylethyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-3-(4-isopropylphenyl)acrylamide-   (397)    (E)-N-(((3S,5S)-3-(2-aminoethyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(4-isopropylphenyl)acrylamide-   (398)    (E)-3-(2,4-dimethylphenyl)-N-(((3S,5S)-1-(2,2-diphenylethyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)acrylamide-   (399)    (E)-N-(((3S,5S)-3-(2-aminoethyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(2,4-dimethylphenyl)acrylamide-   (400)    (E)-3-(2,4-difluorophenyl)-N-(((3S,5S)-1-(2,2-diphenylethyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)acrylamide-   (401)    (E)-N-(((3S,5S)-3-(2-aminoethyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(2,4-difluorophenyl)acrylamide-   (402)    N-(((2S,7S)-7-(((E)-3-(4-chlorophenyl)acrylamido)methyl)-4-(2,2-diphenylethyl)-3-oxo-1,4-diazepan-2-yl)methyl)cyclohexanecarboxamide-   (403)    (E)-3-(4-chlorophenyl)-N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(2-morpholinoethyl)-2-oxo-1,4-diazepan-5-yl)methyl)acrylamide-   (404)    (E)-3-(4-chlorophenyl)-N-(((3S,5S)-3-(2-(2,5-dimethyl-1H-pyrrol-1-yl)ethyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)acrylamide-   (405)    (E)-3-(4-chlorophenyl)-N-(((3S,5S)-3-(2-(2,5-dimethylpyrrolidin-1-yl)ethyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)acrylamide-   (406)    6-chloro-N-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (407)    (E)-3-(4-chlorophenyl)-N-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(pyrrolidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)acrylamide-   (408)    (E)-3-(4-chlorophenyl)-N-(((3S,5S)-3-(2-(isopropylamino)ethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)acrylamide-   (409)    6-chloro-N-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(pyrrolidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (410)    3,4-dichloro-N-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)benzamide-   (411)    3,4-dichloro-N-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(pyrrolidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)benzamide-   (412) benzyl    ((3S,5S)-1-(2,2-diphenylethyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methylcarbamate-   (413)    (E)-3-(4-bromophenyl)-N-(((3S,5S)-1-(2,2-diphenylethyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)acrylamide-   (414)    5-(4-chlorophenyl)-N-(((3S,5S)-1-(2,2-diphenylethyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)isoxazole-3-carboxamide-   (415)    6-chloro-N-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(piperidin-1-ylmethyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (416)    3,4-dichloro-N-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(piperidin-1-ylmethyl)-1,4-diazepan-5-yl)methyl)benzamide-   (417)    6-chloro-N-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(3-(piperidin-1-yl)propyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (418)    3,4-dichloro-N-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(3-(piperidin-1-yl)propyl)-1,4-diazepan-5-yl)methyl)benzamide-   (419)    (E)-N-(2-((3S,5S)-3-(2-aminoethyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)propan-2-yl)-3-(4-chlorophenyl)acrylamide-   (420)    (E)-3-(4-chlorophenyl)-N-(2-((3S,5S)-1-(2,2-diphenylethyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)propan-2-yl)acrylamide-   (421)    N-(((3S,5S)-3-(2-aminoethyl)-1-((R)-2-(4-chlorophenyl)propyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (422)    N-(((3S,5S)-3-(2-aminoethyl)-1-(2-(4-chlorophenyl)propyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (423)    N-(((3S,5S)-1-((R)-2-(4-chlorophenyl)propyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (424)    N-(((3S,5S)-1-((S)-2-(4-chlorophenyl)propyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (425)    3,4-dichloro-N-(((3S,5S)-3-(2-(methyl(phenyl)amino)ethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)benzamide-   (426)    3,4-dichloro-N-(((3S,5S)-3-(2-(diethylamino)ethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)benzamide-   (427)    3,4-dichloro-N-(((3S,5S)-3-(2-morpholinoethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)benzamide-   (428)    3,4-dichloro-N-(((3S,5S)-2-oxo-3-(2-(phenylamino)ethyl)-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)benzamide-   (429)    N-(((3S,5S)-3-(2-(benzylamino)ethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-3,4-dichlorobenzamide-   (430)    N-(((3S,5S)-3-(2-(tert-butylamino)ethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-3,4-dichlorobenzamide-   (431)    3,4-dichloro-N-(((3S,5S)-3-(2-(4-methylpiperazin-1-yl)ethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)benzamide-   (432)    N-(((3S,5S)-2-oxo-1-((R)-2-phenylpentyl)-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (433)    N-(((3S,5S)-2-oxo-1-((S)-2-phenylpentyl)-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (434)    N-(((3S,5S)-1-(2,2-diphenylethyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-4-(trifluoromethyl)benzamide-   (435)    N-(((3S,5S)-3-(2-aminoethyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-4-(trifluoromethyl)benzamide-   (436)    N-(((3S,5S)-1-(2,2-diphenylethyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-3-(trifluoromethyl)benzamide-   (437)    N-(((3S,5S)-3-(2-aminoethyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(trifluoromethyl)benzamide-   (438)    6-chloro-N-(((3S,5S)-1-(3,5-dichlorobenzyl)-3-(2-(isopropylamino)ethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (439)    3,4-dichloro-N-(((3S,5S)-1-(3,5-dichlorobenzyl)-3-(2-(isopropylamino)ethyl)-2-oxo-1,4-diazepan-5-yl)methyl)benzamide-   (440)    6-chloro-N-(((3S,5S)-3-(2-(isopropylamino)ethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (441)    N-(((3S,5S)-3-(2-aminoethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-6-chloro-2-naphthamide-   (442)    N-(((3S,5S)-3-(2-(benzyl(methyl)amino)ethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-3,4-dichlorobenzamide-   (443)    3,4-dichloro-N-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(piperazin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)benzamide-   (444)    3,4-dichloro-N-(((3S,5S)-3-(2-(methyl(pentyl)amino)ethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)benzamide-   (445)    3,4-dichloro-N-(((3S,5S)-3-(2-(diisopropylamino)ethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)benzamide-   (446)    3,4-dichloro-N-(((3S,5S)-3-(2-(4-methylpiperidin-1-yl)ethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)benzamide-   (447)    (S)-6-chloro-N-((2-oxo-1-(2-phenylbutyl)-3-(piperidin-4-yl)-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (448)    (S)-6-chloro-N-(3-(1-isopentylpiperidin-4-yl)-2-oxo-1-(2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (449)    3,4-dichloro-N-(((3S,5S)-3-(2-(3,5-dimethylpiperidin-1-yl)ethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)benzamide-   (450)    3,4-dichloro-N-(((3S,5S)-3-(2-(4-hydroxypiperidin-1-yl)ethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)benzamide-   (451)    1-(2-((2S,7S)-7-((3,4-dichlorobenzamido)methyl)-3-oxo-4-((S)-2-phenylbutyl)-1,4-diazepan-2-yl)ethyl)piperidine-4-carboxylic    acid-   (452)    N-(((3S,5S)-3-(2-(azepan-1-yl)ethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-3,4-dichlorobenzamide-   (453)    3,4-dichloro-N-(((3S,5S)-3-(2-((S)-2-methylpiperidin-1-yl)ethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)benzamide-   (454)    N-(((3S,5S)-3-(2-(tert-butyl(methyl)amino)ethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-3,4-dichlorobenzamide-   (455)    6-chloro-N-((3-(1-ethylpiperidin-4-yl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (456)    (3S,5S)-5-((3,4-dichlorobenzylamino)methyl)-1-(2,2-diphenylethyl)-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-2-one-   (457)    6-chloro-N-(((3S,5S)-3-(2-guanidinoethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (458)    6-chloro-N-(((3S,5S)-3-(2-(3-methylguanidino)ethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (459)    N-(((3S,5S)-3-(2-aminoethyl)-1-((R)-2-ethyl-3-methylbutyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3,4-dichlorobenzamide-   (460)    N-(((3S,5S)-3-(2-aminoethyl)-1-((S)-2-ethyl-3-methylbutyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3,4-dichlorobenzamide-   (461)    3,4-dichloro-N-(((3S,5S)-1-((R)-2-ethyl-3-methylbutyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)benzamide-   (462)    3,4-dichloro-N-(((3S,5S)-1-((S)-2-ethyl-3-methylbutyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)benzamide-   (463)    N-(((3S,5S)-3-(2-amino-2-methylpropyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-6-chloro-2-naphthamide-   (464)    N-(((3S,5S)-3-(2-aminoethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-3,4-dichlorobenzamide-   (465)    3,4-dichloro-N-(((3S,5S)-3-(2-(isopropylamino)ethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)benzamide-   (466)    N-(((3S,5S)-3-(2-aminoethyl)-1-(3,5-dichlorobenzyl)-2-oxo-1,4-diazepan-5-yl)methyl)-6-chloro-2-naphthamide-   (467)    6-chloro-N-(((3S,5S)-1-(3,5-dichlorobenzyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (468)    6-chloro-N-(((3S,5S)-3-(2-methyl-2-(piperidin-1-yl)propyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (469)    N-(((3S,5S)-3-(2-aminoethyl)-1-((R)-2-ethyl-3-methylbutyl)-2-oxo-1,4-diazepan-5-yl)methyl)-6-chloro-2-naphthamide-   (470)    N-(((3S,5S)-3-(2-aminoethyl)-1-((S)-2-ethyl-3-methylbutyl)-2-oxo-1,4-diazepan-5-yl)methyl)-6-chloro-2-naphthamide-   (471)    6-chloro-N-(((3S,5S)-1-((R)-2-ethyl-3-methylbutyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (472)    6-chloro-N-(((3S,5S)-1-((S)-2-ethyl-3-methylbutyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (473)    6-(((3S,5S)-1-(2,2-diphenylethyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methylcarbamoyl)-2-naphthoic    acid-   (474)    6-chloro-N-(((3S,5S)-3-(2-(3-isopropylguanidino)ethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (475)    N-(((3S,5S)-3-(2-aminoethyl)-1-(2-ethyl-3-methylbut-3-enyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3,4-dichlorobenzamide-   (476)    3,4-dichloro-N-(((3S,5S)-1-(2-ethyl-3-methylbut-3-enyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)benzamide-   (477)    N-(((3S,5S)-3-(2-aminoethyl)-1-(2-ethyl-3-methylbut-3-enyl)-2-oxo-1,4-diazepan-5-yl)methyl)-6-chloro-2-naphthamide-   (478)    6-chloro-N-(((3S,5S)-1-((R)-2-ethyl-3-methylbut-3-enyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (479)    6-chloro-N-(((3S,5S)-1-((S)-2-ethyl-3-methylbut-3-enyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (480)    N-(((3S,5S)-1-(cyclohexylmethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)biphenyl-4-carboxamide-   (481)    N-(((3S,5S)-1-(cyclohexylmethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-(1H-indol-3-yl)acetamide-   (482)    N-(((3S,5S)-1-(cyclohexylmethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)quinoline-3-carboxamide-   (483)    3,4-dichloro-N-(((3S,5S)-3-(2-(4,4-difluoropiperidin-1-yl)ethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)benzamide-   (484)    3,4-dichloro-N-(((3S,5S)-3-(2-(3,3-difluoropiperidin-1-yl)ethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)benzamide-   (485)    (3S,5S)-5-((3,4-dichlorobenzylamino)methyl)-1-((S)-2-phenylbutyl)-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-2-one-   (486)    3,4-dichloro-N-(((3S,5S)-1-(2-cyclopropylbutyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)benzamide-   (487)    N-(((3S,5S)-3-(2-aminoethyl)-1-(2-cyclopropylbutyl)-2-oxo-1,4-diazepan-5-yl)methyl)-6-chloro-2-naphthamide-   (488)    6-chloro-N-(((3S,5S)-1-(2-cyclopropylbutyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (489)    3,4-dichloro-N-(((3S,5S)-3-(2-(2,5-dioxopyrrolidin-1-yl)ethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)benzamide-   (490)    6-chloro-N-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(3-ureidopropyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (491)    3,4-dichloro-N-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(1,1,1-trifluoropropan-2-ylamino)ethyl)-1,4-diazepan-5-yl)methyl)benzamide-   (492)    3,4-dichloro-N-(((3S,5S)-3-(2-(3,3-dimethyl-2,5-dioxopyrrolidin-1-yl)ethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)benzamide-   (493)    N-(((3S,5S)-3-(2-(azepan-1-yl)ethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-6-chloro-2-naphthamide-   (494)    6-chloro-N-(((3S,5S)-3-(2-(3-isopropylureido)ethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (495)    N-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)biphenyl-4-carboxamide-   (496)    N-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-phenylthiazole-4-carboxamide-   (497)    4′-chloro-N-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)biphenyl-2-carboxamide-   (498)    6-chloro-N-(((3S,5S)-3-(2-(N-isopropylacetamido)ethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (499)    6-chloro-N-(((3S,5S)-3-((isopropylamino)methyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (500)    6-chloro-N-(((3S,5S)-3-(guanidinomethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (501)    2-(2,4-dichlorophenyl)-N-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)acetamide-   (502)    N-(((3S,5S)-3-(2-aminoethyl)-1-(2,4-dichlorobenzyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3,4-dichlorobenzamide-   (503)    3,4-dichloro-N-(((3S,5S)-1-(2,4-dichlorobenzyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)benzamide-   (504)    3,4-dichloro-N-(((3S,5S)-1-(2,4-dichlorobenzyl)-3-(2-(methylsulfonamido)ethyl)-2-oxo-1,4-diazepan-5-yl)methyl)benzamide-   (505)    3,4-dichloro-N-(((3S,5S)-1-(2,4-dichlorobenzyl)-3-(2-(4-methylphenylsulfonamido)ethyl)-2-oxo-1,4-diazepan-5-yl)methyl)benzamide-   (506)    N-(((3S,5S)-3-(2-((S)-2-amino-3-methylbutanamido)ethyl)-1-(2,4-dichlorobenzyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3,4-dichlorobenzamide-   (507)    N-(((3S,5S)-3-(2-aminoethyl)-1-(2,4-dichlorobenzyl)-2-oxo-1,4-diazepan-5-yl)methyl)-6-chloro-2-naphthamide-   (508)    6-chloro-N-(((3S,5S)-1-(2,4-dichlorobenzyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (509)    N-(((3S,5S)-3-(2-aminoethyl)-2-oxo-1-(2-(thiophen-3-yl)butyl)-1,4-diazepan-5-yl)methyl)-6-chloro-2-naphthamide-   (510)    6-chloro-N-(((3S,5S)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1-((R)-2-(thiophen-3-yl)butyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (511)    6-chloro-N-(((3S,5S)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1-((S)-2-(thiophen-3-yl)butyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (512)    N-(((3S,5S)-3-(2-aminoethyl)-1-(2-ethyl-2-methylbutyl)-2-oxo-1,4-diazepan-5-yl)methyl)-6-chloro-2-naphthamide-   (513)    6-chloro-N-(((3S,5S)-1-(2-ethyl-2-methylbutyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (514)    6-chloro-N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(2-morpholinoethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (515)    6-chloro-N-(((3S,5S)-3-(2-morpholinoethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (516)    6-chloro-N-(((3S,5S)-1-(3,5-dichlorobenzyl)-3-(2-morpholinoethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (517)    3,4-dichloro-N-(((3S,5S)-1-(3,5-dichlorobenzyl)-3-(2-morpholinoethyl)-2-oxo-1,4-diazepan-5-yl)methyl)benzamide-   (518)    N-(3,4-dichlorobenzyl)-N-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)acetamide-   (519)    1-(4-chlorobenzyl)-3-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)urea-   (520)    N-(((3S,5S)-3-(2-aminoethyl)-1-(2-ethyl-2-methylbutyl)-2-oxo-1,4-diazepan-5-yl)methyl)-3,4-dichlorobenzamide-   (521)    3,4-dichloro-N-(((3S,5S)-1-(2-ethyl-2-methylbutyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)benzamide-   (522)    6-chloro-N-(((3S,5S)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1-(2,3,5-trichlorobenzyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (523)    6-chloro-N-(((3S,5S)-3-(2-(1-methylethylsulfonamido)ethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (524) butyl    2-((2S,7S)-7-((6-chloro-2-naphthamido)methyl)-3-oxo-4-((S)-2-phenylbutyl)-1,4-diazepan-2-yl)ethylcarbamate-   (525)    (S)-6-chloro-N-((3-(1-isopropylpiperidin-4-yl)-2-oxo-1-(2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (526)    6-chloro-N-(((3S,5S)-2-oxo-1-((R)-2-phenylbutyl)-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (527)    5-(4-chlorophenyl)-N-(((3S,5S)-1-(3,5-dichlorobenzyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)isoxazole-3-carboxamide-   (528)    2,4-dichloro-N-(((3S,5S)-1-(3,5-dichlorobenzyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)benzamide-   (529)    N-(((3S,5S)-1-(3,5-dichlorobenzyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-6-methoxy-2-naphthamide-   (530)    6-chloro-N-(([5-¹³C,4-¹⁵N](3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)[¹³C]methyl)-2-naphthamide-   (531)    N-(((3S,5S)-1-(3,5-dichlorobenzyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-1-methoxy-2-naphthamide-   (532)    (E)-N-(((3S,5S)-1-(3,5-dichlorobenzyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-3-(4-(trifluoromethoxy)phenyl)acrylamide-   (533)    5-(4-chlorophenyl)-N-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methy)isoxazole-3-carboxamide-   (534)    2,4-dichloro-N-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)benzamide-   (535)    5,6-dichloro-2-(((3S,5S)-1-(3,5-dichlorobenzyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)isoindoline-1,3-dione-   (536)    (E)-N-(((3S,5S)-1-(3,5-dichlorobenzyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-3-(3-fluoro-4-(trifluoromethoxy)phenyl)acrylamide-   (537)    6-methoxy-N-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (538)    1-methoxy-N-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide-   (539)    (E)-3-(3-fluoro-4-(trifluoromethoxy)phenyl)-N-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)acrylamide-   (540)    6-chloro-N-(([5,6,6-²H₃](3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)[²H₂]methyl)-2-naphthamide    or a pharmaceutically acceptable salt or prodrug thereof.    Industrial Utility

As stated previously the compounds of the invention are antagonists ofthe MC5R and therefore may be used to modulate the activity of MC5R or afragment or analogue or functional equivalent thereof by exposing MC5Ror a fragment or analogue or functional equivalent thereof to a compoundof the invention.

Accordingly the compounds of the present invention may be used in thetreatment of any condition in which modulation of the activity of MC5Ror a fragment or analogue or functional equivalent thereof would lead toa beneficial effect on that condition. As such the compounds of theinvention may be used in methods of treating, preventing, or controllinga condition associated either directly or indirectly with the activityof MC5R or a fragment or analogue or functional equivalent thereof in amammal wherein an MC5R modulating amount of the compound of theinvention is administered to the mammal. One condition associated withMC5R activity is excess sebum secretion and conditions related thereto.In one embodiment of the method the condition is selected from the groupconsisting of acne, seborrhoea, and seborrheic dermatitis. In oneembodiment the acne is selected from the group consisting of acnevulgaris, acne, acne conglobata and acne fulminans. In one specificembodiment the condition is acne vulgaris.

For example, downregulation of MC5R leads to a reduction of sebumsecretion and can thus be used in the treatment or prophylaxis of anumber of conditions in which excess sebum secretion is observed such asacne, seborrhoea and seborrheic dermatitis.

The compounds of the present invention may also be useful in thetreatment, prevention or control of a number of conditions that relateto biological processes controlled by MC5R, such as diseases related toinflammation. The compounds may also be useful for the treatment orprevention of cancers, such as Muir-Torre syndrome or other cancers ofthe sebaceous gland.

Due to their impact on sebum secretion the compounds of the presentinvention may also find application in treatments where reduced sebumsecretion is desirable such as in cosmetic treatments. The compounds maythus be used in methods of reducing sebum secretion by a mammal themethod comprising administering an effective amount of a compound offormula (I).

Administration of compounds within Formula (I) to a patient such ashumans can be by topical administration, by any of the accepted modesfor enteral administration such as oral or rectal, or by parenteraladministration such as subcutaneous, intramuscular, intravenous andintradermal routes. Injection can be bolus or via constant orintermittent infusion. The active compound is typically included in apharmaceutically acceptable carrier or diluent and in an amountsufficient to deliver to the patient a therapeutically effective dose.

In using the compounds of the invention they can be administered in anyform or mode which makes the compound bioavailable. One skilled in theart of preparing formulations can readily select the proper form andmode of administration depending upon the particular characteristics ofthe compound selected, the condition to be treated, the stage of thecondition to be treated and other relevant circumstances. We refer thereader to Remingtons Pharmaceutical Sciences, 19^(th) edition, MackPublishing Co. (1995) for further information.

The compounds of the present invention can be administered alone or inthe form of a pharmaceutical composition in combination with apharmaceutically acceptable carrier, diluent or excipient. The compoundsof the invention, while effective themselves, are typically formulatedand administered in the form of their pharmaceutically acceptable saltsas these forms are typically more stable, more easily crystallised andhave increased solubility.

The compounds are, however, typically used in the form of pharmaceuticalcompositions which are formulated depending on the desired mode ofadministration. As such in a further embodiment the present inventionprovides a pharmaceutical composition including a compound of Formula(I) and a pharmaceutically acceptable carrier, diluent or excipient. Thecompositions are prepared in manners well known in the art.

The compounds of formula (I) may be used or administered in combinationwith one or more additional drug (s). The compounds of the presentinvention may be used in combination with one or more otherpharmaceutically-active compounds, such as other anti-acne treatments.In one embodiment the other pharmaceutically active agent is selectedfrom the group consisting of antibiotics, retinoids, anti-androgens, andsteroids. Examples of other pharmaceutically active compounds that maybe combined with a compound of formula (I) and administered inconcurrent or sequential combination therewith may include, by way ofnon-limiting example, other anti-acne agents such as oral retinoids(e.g. isotretinoin), topical retinoids (e.g. isotretinoin, adapalene,tazarotene), oral or topical antibiotics (e.g. clindamycin,erythromycin, minocycline, tetracycline, benzoyl peroxide), or hormonaltherapies (e.g. drospirenone, norgestimate—ethinyl estradiol,cyproterone acetate). As stated these components can be administered inthe same formulation or in separate formulations. If administered inseparate formulations the compounds of the invention may be administeredsequentially or simultaneously with the other drug(s).

A compound of the invention is typically combined with the carrier toproduce a dosage form suitable for the particular patient being treatedand the particular mode of administration. For example, a formulationintended for the oral administration to humans may contain from about0.5 mg to about 5 g of the compound of the invention, compounded with anappropriate and convenient amount of carrier material which may varyfrom about 5 to about 99.95 percent of the total composition.Representative dosage forms will generally contain between from about 1mg to about 500 mg of a compound of the invention, typically 25 mg, 50mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg.Compounds of the present invention may also be formulated for topicaldelivery in formulations such as solutions, ointments, lotions, gels,creams, microemulsions or transdermal patches. For example, thesetopical formulations may contain from 0.005 to 5% (wt/wt or wt/vol) of acompound of the invention.

Pharmaceutical compositions of this invention for parenteral injectioncomprise pharmaceutically acceptable sterile aqueous or nonaqueoussolutions, dispersions, suspensions or emulsions as well as sterilepowders for reconstitution into sterile injectable solutions ordispersions just prior to use. Examples of suitable aqueous andnonaqueous carriers, diluents, solvents or vehicles include water,ethanol, polyols (such as glycerol, propylene glycol, polyethyleneglycol, and the like), and suitable mixtures thereof, vegetable oils(such as olive oil), and injectable organic esters such as ethyl oleate.Proper fluidity can be maintained, for example, by the use of coatingmaterials such as lecithin, by the maintenance of the required particlesize in the case of dispersions, and by the use of surfactants.

These compositions may also contain adjuvants such as preservative,wetting agents, emulsifying agents, and dispersing agents. Prevention ofthe action of micro-organisms may be ensured by the inclusion of variousantibacterial and antifungal agents, for example, paraben,chlorobutanol, phenol sorbic acid, and the like. It may also bedesirable to include isotonic agents such as sugars, sodium chloride,and the like. Prolonged absorption of the injectable pharmaceutical formmay be brought about by the inclusion of agents that delay absorptionsuch as aluminium monostearate and gelatin.

If desired, and for more effective distribution, the compounds can beincorporated into slow release or targeted delivery systems such aspolymer matrices, liposomes, and microspheres.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions that can bedissolved or dispersed in sterile water or other sterile injectablemedium just prior to use.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as calcium carbonate, potato or tapioca starch, alginicacid, certain silicates, and sodium carbonate, e) solution retardingagents such as paraffin, f) absorption accelerators such as quaternaryammonium compounds, g) wetting agents such as, for example, cetylalcohol and glycerol monostearate, h) absorbents such as kaolin andbentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like.

The solid dosage forms of tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions which can beused include polymeric substances and waxes.

If desired, and for more effective distribution, the compounds can beincorporated into slow release or targeted delivery systems such aspolymer matrices, liposomes, and microspheres.

The active compounds can also be in microencapsulated form, ifappropriate, with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups and elixirs. Inaddition to the active compounds, the liquid dosage forms may containinert diluents commonly used in the art such as, for example, water orother solvents, solubilizing agents and emulsifiers such as ethylalcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,dimethyl formamide, oils (in particular, cottonseed, groundnut, corn,germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfurylalcohol, polyethylene glycols and fatty acid esters of sorbitan, andmixtures thereof.

Besides inert diluents, the oral compositions can also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring, and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminiummetahydroxide, bentonite, agar-agar, and tragacanth, and mixturesthereof.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat room temperature but liquid at body temperature and therefore melt inthe rectum or vaginal cavity and release the active compound.

For topical administration, the active agent may be in the form of anointment, cream, suspension, lotion, powder, solution, paste, gel,spray, aerosol or oil. Alternatively, the composition may be deliveredvia a liposome, nanosome, rivosome, or nutri-diffuser vehicle.Alternately, a formulation may comprise a transdermal patch or dressingsuch as a bandage impregnated with an active ingredient and optionallyone or more carriers or diluents. To be administered in the form of atransdermal delivery system, the dosage administration will, of course,be continuous rather than intermittent throughout the dosage regimen.Methods for producing formulations for topical administration are knownin the art.

The compositions used for topical administration typically contain apharmaceutically acceptable carrier which may be any vehicle that istoxicologically and pharmaceutically acceptable. Typicalpharmaceutically acceptable carriers that can be used in compositions ofthe present invention include water, ethanol, acetone, isopropylalcohol, stearyl alcohol, freons, polyvinyl pyrrolidone, propyleneglycol, polyethylene glycol, fragrances, gel-producing materials,mineral oil, stearic acid, spermaceti, sorbitan, monoleate,polysorbates, “Tweens,” sorbitol, methyl cellulose, petrolatum, amineral oil (vaseline oil), which may be any petroleum based product;modified or unmodified vegetable oils such as peanut oil, wheatgerm oil,linseed oil, jojoba oil, apricot kernel oil, walnut oil, palm oil,pistachio oil, sesame oil, colza oil, cade oil, corn germ oil, peachkernel oil, poppyseed oil, pine oil, castor oil, soya oil, saffloweroil, coconut oil, hazelnut oil, grapeseed oil, avocado oil, soy oil,sweet almond oil, calophyllum oil, castor oil, olive oil, sunflower oil,or animal oils such as whale oil, seal oil, menhaden oil, halibut liveroil, cod liver oil, cod, tuna, turtle tallow, horse's hoof, sheep'sfoot, mink, otter, marmot oil and the like; synthetic oils such assilicon oil such as dimethylpolysiloxane; alkyl and alkenyl esters offatty acids, such as isopropyl esters of myristic, palmitic and stearicacids and fatty esters which are solid at room temperature; waxes suchas lanolin wax, candelilla wax, spermaceti, cocoa butter, karite butter,silicon waxes, hydrogenated oils which are solid at room temperature,sucro-glycerides, oleates, myristates, linoleates, stearates, paraffin,beeswax, carnauba wax, ozokerite, candelilla wax, microcrystalline wax;fatty alcohols such as lauryl, cetyl, myristyl, stearyl, palmityl andoleyl alcohols; polyoxyethylated fatty alcohols; and wax esters, lanolinand its derivatives, perhydrosqualene and saturated esters, ethylpalmitate, isopropyl palmitate, alkyl myristates such as isopropylmyristate, butyl myristate and decyl myristate, hexyl stearate,triglyceride esters, triglycerides of octanoic and decanoic acid, cetylricinoleate, stearyl octanoate (Purcellin oil), fatty acids, polyhydricalcohols, polyether derivatives, fatty acid monoglycerides, polyethyleneglycol, propylene glycol, alkyl ethoxy ether sulfonates, ammonium alkylsulfates, fatty acid soaps, and hydrogenated polyisobutene, and mixturesof waxes and oils.

The compositions for topical administration may be formulated innumerous forms. However, the composition may often take the form of anaqueous or oily solution or dispersion or emulsion or a gel or a cream.An emulsion may be an oil-in-water emulsion or a water-in-oil emulsion.

The oil phase of water-in-oil or oil-in-water emulsions may comprise forexample: a) hydrocarbon oils such as paraffin or mineral oils; b) waxessuch as beeswax or paraffin wax; c) natural oils such as sunflower oil,apricot kernel oil, shea butter or jojoba oil; d) silicone oils such asdimethicone, cyclomethicone or cetyldimethicone; e) fatty acid esterssuch as isopropyl palmitate, isopropyl myristate, dioctylmaleate,glyceryl oleate and cetostearyl isononanoate; f) fatty alcohols such ascetyl alcohol or stearyl alcohol and mixtures thereof (eg cetearylalcohol); g) polypropylene glycol or polyethylene glycol ethers, egPPG-14 butyl ether; or h) mixtures thereof.

Emulsifiers used may be any emulsifiers known in the art for use inwater-in-oil or oil-in-water emulsions. Known cosmetically acceptableemulsifiers include: a) sesquioleates such as sorbitan sesquioleate,available commercially for example under the trade name Arlacel 83(ICI), or polyglyceryl-2-sesquioleate; b) ethoxylated esters ofderivatives of natural oils such as the polyethoxylated ester ofhydrogenated castor oil available commercially for example under thetrade name Arlacel 989 (ICI); c) silicone emulsifiers such as siliconepolyols available commercially for example under the trade name ABILWS08 (Th. Goldschmidt AG); d) anionic emulsifiers such as fatty acidsoaps e.g. potassium stearate and fatty acid sulphates e.g. sodiumcetostearyl sulphate available commercially under the trade name Dehydag(Henkel); e) ethoxylated fatty alcohols, for example the emulsifiersavailable commercially under the trade name Brij (ICI);] f) sorbitanesters, for example the emulsifiers available commercially under thetrade name Span (ICI); g) ethoxylated sorbitan esters, for example theemulsifiers available commercially under the trade name Tween (ICI); h)ethoxylated fatty acid esters such as ethoxylated stearates, for examplethe emulsifiers available commercially under the trade name Myrj (ICI);i) ethoxylated mono-, di-, and tri-glycerides, for example theemulsifiers available commercially under the trade name Labrafil (AlfaChem.); j) non-ionic self-emulsifying waxes, for example the waxavailable commercially under the trade name Polawax (Croda); k)ethoxylated fatty acids, for example, the emulsifiers availablecommercially under the trade name Tefose (Alfa Chem.); l) methylglucoseesters such as polyglycerol-3 methyl glucose distearate availablecommercially under the name Tegocare 450 (Degussa Goldschmidt); or m)mixtures thereof.

Gels for topical administration may be aqueous or non-aqueous. Aqueousgels are preferred. The gel will contain a thickening agent or gellingagent in order to give sufficient viscosity to the gel. A variety ofthickening agents may be used according to the nature of the liquidcarrier and the viscosity required and these are recited hereinafter. Aparticularly suitable thickener is a copolymer of acryloyl dimethyltauric acid (or a salt thereof), preferably a copolymer of that monomerwith another vinylic monomer. For example, the thickening agent is acopolymer of a salt of acryloyl dimethyl tauric acid with anothervinylic monomer. The salt may be a salt of a Group I alkali metal, butis more preferably an ammonium salt. Examples of suitable copolymerthickening agents are: i) Ammonium acryloyl dimethyl taurate I vinylpyrrolidone copolymer, ie a copolymer of ammonium acryloyl dimethyltaurate and vinyl pyrrolidone (1-vinyl-2-pyrrolidone).

The composition may additionally comprise other skin care active agentswhich are well known in the art which may be effective to aid the normalfunctioning of the skin. One group of preferred compositions comprisehydrolysed milk protein to regulate sebum production.

The composition may additionally comprise other components which will bewell known to those skilled in the art such as emollients, humectants,emulsion stabilising salts, preservatives, chelating agents orsequestering agents (sequestrants), abrasives, anti-oxidants,stabilisers, pH adjusters, surfactants, thickeners, diluents, perfumesand colourings.

The topical formulations may desirably include a compound that enhancesabsorption or penetration of the active ingredient through the skin orother affected areas. Examples of such dermal penetration enhancersinclude dimethylsulfoxide and related analogues.

Synthesis of Compounds of the Invention

The general synthetic route to the claimed products proceeds through thekey intermediate A, produced as outlined in Schemes 1 or 2.

In Scheme 1, an amino acid derivative V—N(R²)—Y—CO₂H (V=R¹X or an amineprotecting group P¹) is converted to a Weinreb amide via activation ofthe carboxyl group and amidation with N-methyl methoxyamine. Addition ofa vinyl Grignard reagent produces the aminoalkyl vinyl ketone, whichundergoes conjugate addition by the R⁶R⁷R⁸C—(CR^(5a)R^(5b))_(r)NH₂ aminecomponent (shown as WNH₂ for simplicity). The resulting secondary amineis acylated under standard peptide coupling conditions with theprotected amino acid, P²—NHCH(U)—CO₂H, where U represents either thefinal ZNR^(4a)R^(4b) side chain, a protected final side chain, or aprecursor that requires chemical modification to form the finalZNR^(4a)R^(4b) side chain. Deprotection of the P² protecting group isfollowed by intramolecular reductive amination of the ketone usingstandard reduction conditions, such as H₂/Pd catalyst, NaBH₄, NaBH₃CN,or NaBH(OAc)₃, forming key intermediate A. If Y=CH₂ or CH₂CH₂, A isformed as the predominant diastereomer. If V=R¹X and U=ZNR^(4a)R^(4b), Ais the final product.

In Scheme 2, an alternate route to the desired intermediate A beginswith the same Weinreb amide formation, vinyl Grignard addition, andamine conjugate addition. At this point, the secondary amine isprotected with an amine protecting group P⁴. The ketone is thenreductively aminated with a protected amino ester, H₂NCH(U)—CO₂P⁵,producing a mixture of diastereomers that are carried through the nextreaction steps. The ring system is generated by deprotection of the P⁴and P⁵ protecting groups, followed by amide bond formation usingstandard peptide coupling reagents. Alternatively, the P⁴ protectinggroup is removed and cyclization achieved by thermal or base-inducedcyclization with the P⁵-protected ester. The cyclization produces amixture of two diastereomers, A and B, from which the preferreddiastereomer A can be separated by chromatography.

The key intermediate A may be the final product if U=ZNR^(4a)R^(4b) andV=R¹X, but otherwise is converted into the final product as illustratedin Schemes 3, 4 and 5.

In Scheme 3, where V=R¹X, the final product is obtained by modificationof the U side chain, such as removal of a P³ protecting group, orremoval of a P³ protecting group followed by further chemicalmodification.

In Scheme 4, where V=P¹, the final product is obtained by removal of theP¹ protecting group followed by introduction of the R¹X substituent. IfU═ZNR^(4a)R^(4b), this produces the final product. Alternatively, the Uside chain is then modified to produce the final ZNR^(4a)R^(4b) group asin Scheme 3.

In Scheme 5, where V=P¹, the final product is obtained by firstmodifying the U side chain to produce the final ZNR^(4a)R^(4b) group asin Scheme 3. This is followed by removal of the P¹ protecting groupfollowed by introduction of the R¹X substituent.

It is also possible to modify the W substituent, if desired, duringthese reaction sequences.

EXAMPLES

The following examples are intended to illustrate the embodimentsdisclosed and are not to be construed as being limitations thereto.Additional compounds, other than those described below, may be preparedusing the following described reaction schemes as discussed above orappropriate variations or modifications thereof. All starting materialsdescribed in the Examples below are commercially available or readilysynthesized by those skilled in the art.

Instrumentation

HPLC analyses were carried out on an Agilent 1100 Series PurificationSystem with a Phenomenex Synergi 4μ Max-RP 80A, 50×2.00 mm analyticalHPLC column, with peak detection by UV. The standard analysis employed a1 mL/min flow rate of 0.05% trifluoroacetic acid (TFA) in water (SolventA) and 0.05% TFA in 90:10 acetonitrile:water (Solvent B), using agradient of 5% B (initial) to 95% B over 9 min. Mass spectra were run onan Applied Biosystems MDS Sciex API 2000 LC/MS/MS triple quadrupole massspectrometer and analyzed by ion spray mass spectrometry (ISMS).Preparative scale HPLC was carried out on a Waters Delta Prep 3000 HPLCsystem with peak detection by UV (Waters model 486 tunable absorbancedetector), using Phenomenex Luna 10μ C5 100A, 250×21.20 mm (20 mgscale), Phenomenex Luna 15μ C8(2) 100A, 250×30.00 mm (50 mg scale), orPhenomenex Luna 15μ C8(2) 100A, 250×50.00 mm (100 mg scale) HPLCcolumns. The solvent system employed various gradients of 0.05% TFA inwater (Solvent A) and 0.05% TFA in 90:10 acetonitrile:water (Solvent B).

The following examples 1 to 7 provide general synthetic procedures thatmay be followed in order to carry out the transformations described inschemes 1 to 5. In order to make different end products using theseprocedures it is necessary to either vary a variable group on thestarting material or to vary a variable group on one of the reagentsdepending upon the nature of the reaction. It will be apparent to askilled addressee from a reading of the general procedures how to varyeither the starting material or the reagents used in the procedure toproduce differing end products. In addition depending upon the startingmaterials and the reagents it may be necessary and/or desirable to makeslight modifications to the described general procedures in order toprovide the most facile synthesis of the desired end product.

Example 1 General Procedure—Weinreb Amide Formation

BOP reagent (100 mmol) and diisopropylethylamine (DIPEA) (100 mmol) isadded to a stirred solution of the amino acid (1) (100 mmol) indichloromethane (DCM) (100 mL). The solution is then stirred at roomtemperature for 10 mins, before addition of a premixed solution ofN,O-dimethylhydroxylamine hydrochloride (100 mmol) and DIPEA (100 mmol)followed by stirring at room temperature overnight. The DCM is thenremoved by rotary evaporation and the residue taken up in ethyl acetate(EtOAc) (200 mL). The organic phase is then washed with 1N HCl (3×100mL), H₂O (3×100 mL), saturated NaHCO₃ aqueous solution (3×100 mL) andbrine (1×10 mL). The organic phase is then dried (MgSO₄) and the EtOAcremoved to give the Weinreb amide (2) as a white solid or an oil.

Example 2 General Procedure—Vinyl Grignard Addition to Weinreb Amide toForm α,β-Unsaturated Ketones of Formula (3)

To the Weinreb amide (2) (15 mmol) in DCM (10 mL) at 0° C. is addedvinyl magnesium bromide (45 mmol) in THF (45 mL). The reaction isstirred for 2 hrs and monitored by HPLC. The reaction is then quenchedby adding it to a mixture of ice and 1M HCl (200 mL). The aqueousmixture is extracted with DCM (3×100 mL) and the organic layers combinedand washed with 1M HCl (2×200 mL) and H₂O (3×100 mL). The organic phaseis dried (MgSO₄) to provide a solution of the α,β-unsaturated ketone(3). The α,β-unsaturated ketone (3) may be isolated by rotaryevaporation or it may be used in solution without further purification.If the intention is to use the α,β-unsaturated ketone (3) in solutionthe volume is reduced to 100 mL by rotary evaporation and stored forlater use.

Example 3 General Procedure—Conjugate Addition of Amine toα,β-Unsaturated Ketones of Formula (3) to Produce Compounds of Formula(4)

To the amine W—NH₂ (7.4 mmol) in DCM (10 mL) is added a solution of theα,β-unsaturated ketone (3) (5.7 mmol) in DCM (50 mL). The solution isstirred at room temperature for 15 mins, or until analysis indicatesthat all of (3) has been consumed. The solution of compound (4) isimmediately used without purification for the subsequent reaction.

Example 4 General Procedure—Acylation of Aminoketone (4)

The amine acid P²—NHCH(U)—CO₂H (15 mmol) and DIC (15 mmol) is added to asolution of DCM containing 10 mmol of the conjugate addition adduct 4.The reaction is stirred at room temperature overnight. The DCM isremoved by rotary evaporation and the residue is then subjected tocolumn chromatography on silica gel using petroleum spirit:EtOAc to give5.

As an alternative, the DIC may be replaced with HATU (15 mmol) and DIPEA(15 mmol). The reaction is stirred at room temperature overnight. TheDCM is removed by rotary evaporation and the residue is taken up inEtOAc (100 mL). The organic layer is washed with saturated sodiumbicarbonate solution (2×100 mL), saturated ammonium chloride solution(2×100 mL) and brine (2×100 mL). The organic phase is dried and thesolvent removed under reduced pressure. The residue is subjected tocolumn chromatography on silica gel using petroleum ether:EtOAc to give5.

Example 5 General Procedure—P² Deprotection and Cyclization

The procedure adopted for the removal of the P2 protecting group willvary depending upon the exact nature of the protecting group. As will beappreciated by a skilled addressee a large number of possible protectinggroups may be used and a skilled worker in the art will readily be ableto determine an appropriate procedure for the removal of any particularprotecting group from procedures known in the art. Nevertheless in orderto assist the reader general procedures for the removal of the morecommon protecting groups are provided.

-   P²=Fmoc: To compound 5 (2 mmol) in DCM (3 mL) is added diethylamine    (20 mmol). The reaction is stirred at room temperature for 1 hr. The    DCM and diethylamine is then removed by rotary evaporation. DCM (5    mL) and sodium triacetoxyborohydride (3 mmol) are then added, and    the reaction stirred overnight at room temperature. The organic    phase is washed with saturated sodium bicarbonate solution (25 mL),    dried (MgSO₄) and the DCM removed to give the cyclised product A.    This may be purified by flash chromatography on silica gel or used    without purification.-   P²=Boc: To compound 5 (2 mmol) in DCM (3 mL) is added TFA (3 mL) and    the reaction stirred at room temperature for 2 hrs. The DCM and TFA    are then removed by rotary evaporation. DCM (5 mL) and sodium    triacetoxyborohydride (3 mmol) is then added, and the reaction    stirred overnight at room temperature. The organic phase is washed    with saturated sodium bicarbonate solution (25 mL), dried (MgSO₄)    and the DCM removed to give the cyclised product A. This may be    purified by flash chromatography on silica gel or used without    purification.-   P²=Cbz: A mixture of crude 5 (1 mmol) and 5% Pd/C (200 mg) in    2-propanol (15 mL) is shaken at room temperature under hydrogen (30    psi) for 24 hrs. The mixture is then filtered through a pad of    Celite and the filtrate concentrated under reduced pressure to give    a crude product. Purification by flash chromatography on silica gel    (100% EtOAc) may be used to give A.

Example 6 General Procedure—P¹ Deprotection and Derivatization with R¹X

The procedure adopted for the removal of the P1 protecting group willvary depending upon the exact nature of the protecting group. As will beappreciated by a skilled addressee a large number of possible protectinggroups may be used and a skilled worker in the art will readily be ableto determine an appropriate procedure for the removal of any particularprotecting group from procedures known in the art. Nevertheless in orderto assist the reader general procedures for the removal of the morecommon protecting groups are provided.

-   Deprotection, P¹=Cbz:-   To the cyclised product A (1 mmol) in methanol (5 mL) is added    catalytic Pd/C. The reaction is stirred under a hydrogen atmosphere    overnight. The reaction mixture is filtered through Celite and the    methanol removed by rotary evaporation to give the free amine. The    amine may be used in the next reaction without purification.-   Deprotection, P¹=Boc:-   To the cyclised product A (1 mmol) in DCM (1 mL) is added TFA (1 mL)    and the reaction stirred at room temperature for 2 hrs. The solvent    is removed by rotary evaporation to give the amine TFA salt, which    may be used in the next reaction without purification.-   Deprotection, P¹=Alloc:-   To the cyclised product A (1 mmol) in DCM (6 mL) is added    1,3-dimethylbarbituric acid (0.2 mmol) and palladium tetrakis    triphenylphosphine (10 mg). The reaction is evacuated and stirred at    room temperature for 1 hr. The DCM is removed under reduced pressure    to give the crude free amine, which may be used in the next reaction    without purification.-   Derivatisation with R¹X when X═C(═O):-   To the free amine (1 mmol) in DCM (5 mL) is added DIPEA (1 mmoL),    BOP reagent (1.5 mmol) and acid component R¹CO₂H (1.5 mmol). The    reaction is stirred at room temperature for 2 hrs. Rotary    evaporation and preparative HPLC gives the purified adduct.

Example 7 General Procedure—U Modification via P³ Deprotection andDialkylation with Dibromide

The procedure adopted for modification of U via deprotection andderivatization will vary depending on the exact nature of the U group.As will be appreciated by a skilled addressee a large number ofmodifications are possible, and a skilled worker in the art will readilybe able to determine an appropriate procedure for the conversion into adesired R group. Nevertheless in order to assist the reader, one generalmodification procedure commonly employed for a number of the followingexamples is provided.

P³=Boc:

To the protected amine (1 mmol) in DCM (5 mL) is added TFA (5 mL) andthe reaction stirred at room temperature for 2 hrs. DCM (20 mL) is addedand the solution is washed with saturated sodium bicarbonate solution(20 mL), dried (MgSO₄) and evaporated to give the crude amine. To thecrude amine is added DMF (0.5 mL), potassium carbonate (50 mg) and1,5-dibromopentane (5 mmol). The reaction mixture is stirred at roomtemperature for 1.5 hrs, after which DCM (20 mL) is added, the organiclayer washed with saturated sodium bicarbonate solution (20 mL) and H₂O(20 mL), dried (MgSO₄) and evaporated. The residue may be purified bypreparative HPLC to give the piperidinyl product. The purified productis isolated as the TFA salt, but is readily converted into the free basevia neutralisation with aqueous NaHCO₃ and extraction into an organicsolvent, or further converted into the HCl salt by acidification with 1NHCl.

Example 8 Synthesis of Compound 8N-(2-(methoxy(methyl)amino)-2-oxoethyl)-2-naphthamide

To a mixture of 2-naphthoic acid (5.8 g, 33.7 mmol),2-amino-N-methoxy-N-methylacetamide (Gly Weinreb amide; prepared fromBoc-Gly Weinreb amide 15 as in Example 44) (3.8 g, 32.1 mmol) and DIPEA(12.0 mL, 68.9 mmol) in DCM (70 mL) was added BOP (14.9 g, 33.7 mmol) inone portion at room temperature. The resulting mixture was stirred for 1hr then saturated NaHCO₃ aqueous solution was added. The organic layerwas washed with brine (5×60 mL) and 1 N HCl (2×30 mL), dried over MgSO₄,filtered and concentrated under reduced pressure to give the crudeproduct, which was used in the next reaction without furtherpurification.

Example 9 Synthesis of Compound 9N-(2-(methoxy(methyl)amino)-2-oxoethyl)-2-naphthamide

To a solution of 8 (3.5 g, 12.85 mmol) in dry THF (10 mL) was added asolution of vinylmagnesium bromide in THF (1 M, 31 mL) slowly at 0° C.After addition, the resulting mixture was stirred at room temperaturefor 1 hr then was poured into an icy 1 N HCl solution (50 mL). Theaqueous layer was extracted with DCM (3×80 mL) and the combined organiclayers were dried over MgSO₄, filtered and concentrated under reducedpressure to give the crude product. MS (ESI) 240 (M+1); HPLC t_(R) 5.46min.

Example 10 Synthesis of Compound 10N-(4-(3,5-dichlorobenzylamino)-2-oxobutyl)-2-naphthamide

To a solution of 3,5-dichlorobenzylamine (12 mg, 0.068 mmol) in DCM (0.2mL) was added a solution of 9 (13 mg, 0.054 mmol) in DCM (0.5 mL) atroom temperature. The resulting mixture was stirred until all of the 9had been consumed (within one hr) and then was used straight in the nextreaction. MS (ESI) 415 (M+1); HPLC t_(R) 6.00 min.

Example 11 Synthesis of Compound 11(S)—N-(4-(5-(3-Pbf-guanidino)-2-(Fmoc-amino)-N-(3,5-dichlorobenzyl)pentanamido)-2-oxobutyl)-2-naphthamide

To a solution of freshly prepared aminoketone 10 in DCM (2 mL) was addedFmoc-L-Arg(Pbf)-OH (53 mg, 0.082 mmol) followed by DIC (12.5 μl, 0.082mmol) at room temperature. The resulting mixture was stirred for 2 hrsthen the solvent was removed under reduced pressure. The residue wasfiltered through a short plug of silica gel eluting with DCM followed byEtOAc to give the desired product 11 as a white solid. It was used inthe next step without further purification. MS (ESI) 1045 (M+1); HPLCt_(R) 9.99 min.

Example 12 Synthesis of Compound 12(S)—N-(4-(5-(3-Pbf-guanidino)-2-amino-N-(3,5-dichlorobenzyl)pentanamido)-2-oxobutyl)-2-naphthamide

Diethylamine (0.5 mL) was added to Fmoc-protected 11 (56 mg, 0.054 mmol)at room temperature and the resulting mixture was stirred for 30 min.The excess amount of the diethylamine was removed under reduced pressureto give the desired free amine 12. It was used in the next step withoutfurther purification. MS (ESI) 823 (M+1); HPLC t_(R) 7.49 min.

Example 13 Synthesis of Compound 13N-(((3S,5S)-3-(3-(3-Pbf-guanidino)propyl)-1-(3,5-dichlorobenzyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide

The amino ketone 12 (44 mg, 0.053 mmol) in DCM (2 mL) was cyclized byaddition of NaBH(OAc)₃ (40 mg, 0.18 mmol) in one portion at roomtemperature. The resulting mixture was stirred for 3 hrs, followed byaddition of saturated NaHCO₃ aqueous solution (3 mL). The aqueous layerwas extracted with DCM (3×3 mL) and the combined organic layers weredried over MgSO₄, filtered and concentrated under reduced pressure. Theresidue was filtered through a short plug of silica gel eluting with DCMfollowed by EtOAc then EtOAc/IPA (9:1) to give the desired product 13 asa white solid. It was used in the next step without furtherpurification. MS (ESI) 807 (M+1); HPLC t_(R) 7.75 min.

Example 14 Synthesis of Compound 14N-(((3S,5S)-1-(3,5-dichlorobenzyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide

A solution of TFA/DCM (2:1) (1 mL) with 5% H₂O was added to 13 at roomtemperature and the resulting mixture was stirred for 4 hrs. Thesolvents were removed under reduced pressure and the residue waspurified by prep HPLC (100% H₂O to acetonitrile/H₂O 9:1, gradient) togive 14 (7.6 mg) as a white solid (TFA salt). The overall yield (from 9)was ca. 18%. MS (ESI) 556.2 (M+1); HPLC t_(R) 5.74 min.

Example 15 Synthesis of Compound 15 tert-butyl2-(methoxy(methyl)amino)-2-oxoethylcarbamate (Boc-Gly Weinreb amide)

To a stirred mixture of Boc-Gly-OH (20 g, 114.1 mmol), DIPEA (19.8 mL,114.1 mmol) and BOP (50.5 g, 114.1 mmol) in DCM (20 mL) was added apre-mixed solution of N,O-dimethylhydroxylamine hydrochloride (11.2 g,114.1 mmol) and DIPEA (19.8 mL, 114.1 mmol) in DCM (20 mL) at roomtemperature. The resulting mixture was stirred for 16 h then washed with1N HCl (3×120 mL), H₂O (3×120 mL), saturated NaHCO₃ aqueous solution(3×120 mL) and brine (40 mL), dried over MgSO₄, filtered andconcentrated under reduced pressure to give 15 as a white solid (20 g,80%), which was used in the next step without further purification. MS(ESI) 219 (M+1); HPLC t_(R) 4.12 min.

Example 16 Synthesis of Compound 16 tert-butyl 2-oxobut-3-enylcarbamate

At 0° C. a solution of vinylmagnesium bromide in THF (184 mL, 1 M) wasadded in one portion to Weinreb amide 15 (20 g, 91.6 mmol) undernitrogen with stirring. The resulting mixture was allowed to stir for 2h, and poured into a 1N HCl/ice mixture (400 mL). The aqueous mixturewas extracted with DCM (5×100 mL), the combined DCM extract was washedwith 1N HCl (2×100 mL), saturated NaHCO₃ aqueous solution (100 mL) andbrine (100 mL), then dried over MgSO₄. Solvent was removed under reducedpressure gave the ketone 16 (12.9 g, 76%) as a pale yellow oil, whichwas used in the next step without further purification. MS (ESI) 186(M+1); HPLC t_(R) 4.19 min.

Example 17 Synthesis of Compound 17 tert-butyl4-(2,2-diphenylethylamino)-2-oxobutylcarbamate

To a stirred solution of 2,2-diphenylethylamine (0.33 g, 1.66 mmol) inDCM (10 mL) was added α,β-unsaturated ketone 16 (0.31 g, 1.66 mmol) atroom temperature. Stirring continued for 2 h; the crude reaction mixtureof 17 was used in the next step without purification. MS (ESI) 383(M+1); HPLC t_(R) 5.98 min

Example 18 Synthesis of Compound 18 (S)-tert-butyl3-methyl-4,8-dioxo-10-phenyl-2,9-dioxa-3,7-diazadecane-6-carboxylate

To a suspension of Cbz-L-Asp-OtBu DCHA salt (10.1 g, 20.0 mmol),N,O-dimethylhydroxylamine-HCl (5.9 g, 60.5 mmol) and DIPEA (12.0 mL,68.9 mmol) in DCM (150 mL) was added BOP (10.6 g, 24.0 mmol) in oneportion at room temperature. The resulting suspension was stirred for 3hrs then H₂O (100 mL) was added. The organic layer was washed with 1 NHCl (2×100 mL), saturated NaHCO₃ aqueous solution (2×100 mL) and brine(3×100 mL) and then dried over MgSO₄, filtered and concentrated underreduced pressure to give the crude product. Purification by flashchromatography on silica gel (PET ether/EtOAc 1:2) gave 18 (6.4 g, 87%)as a colorless oil. MS (ESI) 367 (M+1); HPLC t_(R) 6.87 min.

Example 19 Synthesis of Compound 19(S)-3-methyl-4,8-dioxo-10-phenyl-2,9-dioxa-3,7-diazadecane-6-carboxylicacid

Compound 18 (300 mg, 0.82 mmol) was dissolved in a TFA/DCM (1:1)solution (2 mL) and the resulting mixture was stirred at roomtemperature for 2 hrs. The solvents were removed under reduced pressureand the residue was re-dissolved in DCM (10 mL). This solution waswashed with 1 N HCl (1×10 mL) and the organic layer was dried overMgSO₄, filtered and concentrated under reduced pressure to give thecrude product 19 (235 mg, 92%), which was used in the next reactionwithout further purification. MS (ESI) 311 (M+1); HPLC t_(R) 4.96 min.

Example 20 Synthesis of Compound 20 (S)-benzyl8-(2,2-diphenylethyl)-3,16,16-trimethyl-4,7,11,14-tetraoxo-2,15-dioxa-3,8,13-triazaheptadecan-6-ylcarbamate

Compound 20 was prepared from Compound 17 and 19 following the procedureof Example 4. MS (ESI) 675 (M+1); HPLC t_(R) 8.31 min.

Example 21 Synthesis of Compound 21 tert-butyl((3S,5S)-1-(2,2-diphenylethyl)-3-(2-(methoxy(methyl)amino)-2-oxoethyl)-2-oxo-1,4-diazepan-5-yl)methylcarbamate

A mixture of crude 20 (350 mg) and 5% Pd/C (200 mg) in 2-propanol (15mL) was shaken at room temperature under hydrogen (30 psi) for 24 hrs.The mixture was then filtered through a pad of Celite and the filtratewas concentrated under reduced pressure to give the crude product.Purification by flash chromatography on silica gel (100% of EtOAc) gave21 (175 mg, 65% over 3 steps) as a white solid. MS (ESI) 525 (M+1); HPLCt_(R) 6.24 min.

Example 22 Synthesis of Compound 222-((2S,7S)-7-(aminomethyl)-4-(2,2-diphenylethyl)-3-oxo-1,4-diazepan-2-yl)-N-methoxy-N-methylacetamide

Compound 21 (175 mg, 0.333 mmol) was dissolved in a TFA/DCM (1:1)solution (1 mL) and the resulting mixture was stirred at roomtemperature for 2 hrs. The solvents were removed under reduced pressureand the residue was re-dissolved in EtOAc (20 mL). Saturated NaHCO₃aqueous solution (10 mL) and brine (10 mL) were added to the abovesolution and the aqueous layer was extracted with EtOAc (9×20 mL). Thecombined organic layers were dried over MgSO₄, filtered and concentratedunder reduced pressure to give the crude product 22 (120 mg, 85%) as ayellow solid, which was used in the next reaction without furtherpurification. MS (ESI) 425 (M+1); HPLC t_(R) 5.20 min.

Example 23 Synthesis of Compound 23N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(2-(methoxy(methyl)amino)-2-oxoethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-6-fluoro-2-naphthamide

To a solution of 22 (50 mg, 0.118 mmol) and 6-fluoro-2-naphthoic acid(27 mg, 0.142 mmol) in DCM (4 mL) was added DIC (22 μl, 0.142 mmol) atroom temperature. The resulting mixture was stirred for 2 hrs then thesolvent was removed under reduced pressure to give the crude product.Purification by flash chromatography on silica gel (eluting withPetroleum ether:EtOAc (1:1) then EtOAc) gave 23 (29 mg, 41%) as a whitesolid. MS (ESI) 597 (M+1); HPLC t_(R) 6.75 min.

Example 24 Synthesis of Compound 24N-(((3S,5S)-1-(2,2-diphenylethyl)-2-oxo-3-(2-oxoethyl)-1,4-diazepan-5-yl)methyl)-6-fluoro-2-naphthamide

To a solution of 23 (29 mg, 0.049 mmol) in dry THF (1 mL) was addedLiAlH(OtBu)₃ (38 mg, 0.145 mmol) in one portion at room temperature andthe resulting suspension was stirred overnight. This suspension was thenslowly poured into a cold (0° C.) 0.4 M KHSO₄ aqueous solution (2 mL,0.8 mmol) and the resulting mixture was diluted with EtOAc (3 mL). Theaqueous layer was extracted with EtOAc (3×3 mL) and the combined organiclayers were washed with 1 N HCl (3×6 mL), saturated NaHCO₃ aqueoussolution (1×6 mL), and brine (1×6 mL). The organic solution was thendried over MgSO₄, filtered and concentrated under reduced pressure togive the crude product 24 (24 mg, 91%), which was used in the nextreaction without further purification. MS (ESI) 538 (M+1); HPLC t_(R)6.41 min.

Example 25 Synthesis of Compound 25N-(((3S,5S)-3-(2-(diethylamino)ethyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-6-fluoro-2-naphthamide

To a solution of 24 (24 mg, 0.044 mmol) in DCM (2 mL) was addeddiethylamine (55 μl, 0.532 mmol) at room temperature. After stirring for5 mins, NaBH(OAc)₃ (20 mg, 0.090 mmol) was added to the above solutionin one portion and the resulting suspension was stirred for another 10mins. Saturated NaHCO₃ aqueous solution (4 mL) was added to thesuspension and the aqueous layer was extracted with DCM (3×4 mL). Thecombined organic layers were washed with brine (10 mL), dried overMgSO₄, filtered and concentrated under reduced pressure to give thecrude product. This crude product was purified by prep HPLC (100% H₂O to90:10 acetonitrile:H₂O, gradient) to give the 25 as a white solid (TFAsalt). MS (ESI) 595.3 (M+1); HPLC t_(R) 6.22 min.

Example 26 Synthesis of Compound 26 benzyl2-(methoxy(methyl)amino)-2-oxoethylcarbamate

To Cbz-glycine (10 g, 47.8 mmol, Aldrich) in DCM (100 mL) was added BOPreagent (21.5 g, 48.6 mmol) and DIPEA (6.5 mL, 46.0 mmol). Afterstirring at room temperature for 10 mins, N,O-dimethylhydroxylaminehydrochloride (4.9 g, 50.2 mmol) and DIPEA (6.5 mL, 46.0 mmol) wereadded. The reaction was stirred at room temperature overnight. The DCMwas removed by rotary evaporation and the residue taken up in EtOAc (100mL). The organic phase was washed with H₂O (3×100 mL), saturated sodiumbicarbonate solution (3×100 mL), H₂O (3×100 mL), 1M hydrochloric acid(3×100 mL), brine (3×100 mL). The organic phase was dried (MgSO₄) andthe EtOAc removed to give the Weinreb amide 26 as a white solid (7.78 g,64%).

Example 27 Synthesis of Compound 27 benzyl 2-oxobut-3-enylcarbamate

To the Weinreb amide 26 (3.89 g, 15.42 mmol) in DCM (10 mL) at 0° C. wasadded vinyl magnesium bromide (45 mmol) in THF (45 mL). The reaction wasstirred for 2 hrs and monitored by HPLC. The reaction was added to amixture of ice and 1M hydrochloric acid (200 mL). The aqueous mixturewas extracted with DCM (3×100 mL) and washed with 1M hydrochloric acid(2×200 mL) and H₂O (3×100 mL). The organic phase was dried (MgSO₄) andthe volume reduced to 100 mL by rotary evaporation. The α,β-unsaturatedketone 27 was stored and used in solution without purification.

Example 28 Synthesis of Compound 28 (S)-9-fluorenylmethyl10-(2,2-diphenylethyl)-2,2-dimethyl-18-phenyl-4,9,13,16-tetraoxo-3,17-dioxa-5,10,15-triazaoctadecan-8-ylcarbamate

To 2,2-diphenylethylamine (0.95 g, 7.4 mmol) in DCM (10 mL) was addedthe α,β-unsaturated ketone 27 (5.7 mmol) in DCM (75 mL). After stirringat room temperature for 15 mins, Fmoc-L-2,4-diaminobutyric acid(Boc)-OH(2.4 g, 8.55 mmol) and DIC (0.87 mL, 5.6 mmol) were added. The reactionwas stirred at room temperature overnight. The DCM was removed by rotaryevaporation and the residue was subjected to column chromatography onsilica gel using petroleum ether:EtOAc (1:1 to 0:1) to give 28 (1.5 g,31%)

Alternatively, to 2,2-diphenylethylamine (0.97 g, 7.4 mmol) in DCM (20mL) was added the α,β-unsaturated ketone 27 (5.95 mmol) in DCM (40 mL).After stirring at room temperature for 15 mins,Fmoc-L-2,4-diaminobutyric acid(Boc)-OH (2.4 g, 8.55 mmol), DIPEA (2.5mL) and HATU (2.3 g, 6.0 mmol) were added. The reaction was stirred atroom temperature overnight. The DCM was removed by rotary evaporationand the residue was taken up in EtOAc (100 mL). The organic layer waswashed with saturated sodium bicarbonate solution (2×100 mL), saturatedammonium chloride solution (2×100 mL) and brine (2×100 mL). The organicphase was dried and the solvent removed under reduced pressure. Theresidue was subjected to column chromatography on silica gel usingpetroleum ether:EtOAc (3:1 to 1:1 to 0:1) to give 28 (0.86 g, 17%).

Example 29 Synthesis of Compound 29(3S,5S)-3-(2-tert-butoxycarbonylaminoethyl)-5-(benzyloxycarbonylaminomethyl)-1-(2,2-diphenylethyl)-1,4-diazepan-2-one

To Compound 28 (1.5 g, 1.8 mmol) in DCM (3 mL) was added diethylamine(1.5 mL, 14.5 mmol). The reaction was stirred at room temperature for 1hr. The DCM and diethylamine was removed by rotary evaporation. DCM (5mL), sodium triacetoxyborohydride (0.4 g, 1.9 mmol) was added, and thereaction was stirred overnight at room temperature. The organic phasewas washed with saturated sodium bicarbonate solution (25 mL), dried(MgSO₄) and the DCM removed to give the cyclised product 29, which wasused in the next step without purification.

Example 30 Synthesis of Compound 30(3S,5S)-3-(2-tert-butoxycarbonylaminoethyl)-5-aminomethyl-1-(2,2-diphenylethyl)-1,4-diazepan-2-one

To the cyclised product 29 in methanol (5 mL) was added catalytic Pd/C.The reaction was stirred under a hydrogen atmosphere overnight. Thereaction mixture was filtered through Celite and the methanol removed byrotary evaporation to give the amine 30 (0.7 g, 83% from 28).

Example 31 Synthesis of Compound 31N-(((3S,5S)-3-(2-aminoethyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-6-fluoro-2-naphthamide

To the amine 30 (0.08 g, 0.17 mmol) in DCM (1 mL) was added DIPEA (0.25mL), BOP reagent (0.08 g, 0.18 mmol) and 6-fluoro-2-naphthoic acid (0.06g, 0.32 mmol). The reaction was stirred at room temperature for 2 hrs.TFA (1 mL) was added and the reaction stirred at room temperature for 2hrs. Rotary evaporation and preparative HPLC gave 31 (0.05 g, 54%). MS(ESI) 539.3 (M+1); HPLC t_(R) min 5.92

Example 32 Synthesis of Compound 32 6-chloro-2-naphthoic acid

A suspension of 6-bromo-2-naphthoic acid (3.0 g, 11.47 mmol), CuCl (11.7g, 114.64 mmol) and CuI (2.19 g, 11.50 mmol) in degassed DMF (45 mL) washeated to reflux under argon in dark for 4 hrs. After cooling to roomtemperature, the solution was decanted into H₂O (200 mL) and theresulting mixture was extracted with EtOAc (2×500 mL). The combinedorganic layers were then washed with H₂O (4×500 mL) followed by brine(1×500 mL), dried over MgSO₄, filtered and concentrated under reducedpressure to dryness. The residue was trituated with CH₃CN and the solidobtained was then re-crystallized from EtOAc to give the pure product 32(2.2 g, 93%) as an off-white solid. HPLC t_(R) 6.47 min.

Example 33 Synthesis of Compound 33(E)-3-(4-chlorophenyl)-N-(((3S,5S)-1-(2,2-diphenylethyl)-2-oxo-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)acrylamide

To the amine(E)-3-(4-chlorophenyl)-N-(((3S,5S)-1-(2,2-diphenylethyl)-2-oxo-3-(2-aminoethyl)-1,4-diazepan-5-yl)methyl)acrylamide(21 mg, 0.05 mmol) in DMF (0.25 mL) was added K₂CO₃ (5 mg) and1,5-dibromopentane (0.066 mL, 0.5 mmol). The reaction mixture was leftat room temperature for 4 hrs. The solvent was removed under highvacuum, and the residue purified by preparative HPLC to give 8 mg (˜30%)of 33 as the TFA salt. MS (ESI) 599.4 (M+1)); HPLC t_(R) min 6.31

Example 34 Synthesis of Compound 34 (S)-9-fluorenylmethyl10-(2-phenylbutyl)-2,2-dimethyl-18-phenyl-4,9,13,16-tetraoxo-3,17-dioxa-5,10,15-triazaoctadecan-8-ylcarbamate

To 2-phenylbutylamine hydrochloride (0.26 g, 1.4 mmol) in DCM (10 mL)and DIPEA (0.25 mL, 1.8 mmol) was added the α,β-unsaturated ketone 27(1.06 mmol) in DCM (20 mL). After stirring at room temperature for 15mins, Fmoc-diaminobutyric acid(Boc)-OH (0.7 g, 1.56 mmol) and DIC (0.25mL, 1.61 mmol) were added. The reaction was stirred at room temperatureovernight. The DCM was removed by rotary evaporation and the residue wassubjected to column chromatography on silica gel using petroleumether:EtOAc (1:1 to 0:1), providing Compound 34 as a mixture ofdiastereomers (0.17 g, 21%).

Example 35 Synthesis of Compound 35(3S,5S)-3-(2-tert-butoxycarbonylaminoethyl)-5-(benzyloxycarbonylaminomethyl)-1-(2-phenylbutyl)-1,4-diazepan-2-one

To Compound 34 (0.17 g, 0.2 mmol) in DCM (3 mL) was added diethylamine(1.5 mL). The reaction was stirred at room temperature for 1 hr. The DCMand diethylamine was removed by rotary evaporation. DCM (5 mL) andsodium triacetoxyborohydride (0.1 g, 0.47 mmol) were added and thereaction was stirred overnight at room temperature. The organic phasewas washed with saturated sodium bicarbonate solution (25 mL), dried(MgSO₄) and the DCM removed to give the cyclised product 35 as a mixtureof diastereomers (0.11 g, 100%).

Example 36 Synthesis of Compound 36(3S,5S)-3-(2-tert-butoxycarbonylaminoethyl)-5-(aminomethyl)-1-(2-phenylbutyl)-1,4-diazepan-2-one

To the cyclised product 35 (0.11 g) in methanol (5 mL) was addedcatalytic Pd/C. The reaction was stirred under a hydrogen atmosphereovernight. The reaction mixture was filtered through Celite and themethanol removed by rotary evaporation to give the amine 36 as a mixtureof diastereomers (0.11 g, 100%).

Example 37 Synthesis of Compound 37(3S,5S)-3-(2-aminoethyl)-5-(N-2-naphthamidomethyl)-1-(2-phenylbutyl)-1,4-diazepan-2-one

To the amine 36 (0.02 mg, 0.05 mmol) in DCM (1 mL) was added DIPEA (0.1mL, 0.7 mmol), BOP reagent (0.02 mg, 0.045 mmol) and 2-naphthoic acid(0.015 mg, 0.09 mmol). The reaction was stirred at room temperature for2 hrs. TFA (1 mL) was added and the reaction stirred at room temperaturefor 2 hrs. Rotary evaporation and preparative HPLC gave 37 as a mixtureof diastereomers (13.4 mg, 57%). MS (ESI) 473.4 (M+1); HPLC t_(R) 5.59min

Example 38 Synthesis of Compounds 38-39N-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naphthamideandN-(((3S,5S)-2-oxo-1-((R)-2-phenylbutyl)-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide

Prepared from Compound 37 by alkylation as in Example 33. PreparativeHPLC purification separated the two diastereomers. The correctconfiguration was assigned by resynthesis of the compounds using(S)-2-phenylbutylamine 43 or (R)-2-phenylbutylamine. 38: MS (ESI) 541.3(M+1); HPLC t_(R) 5.78 min; 39: MS (ESI) 541.3 (M+1); HPLC t_(R) 5.67min

Example 39 Synthesis of Compound 40 (S)-2-phenylbutanol

To a suspension of sodium borohydride (2.36 g, 62.4 mmol) in THF (50 mL)was added a solution of (S)-2-phenylbutyric acid (4.27 g, 26.0 mmol) inTHF (40 mL) slowly at 0° C. The mixture was stirred until the evolutionof gas ceased. A solution of iodine (6.60 g, 26.0 mmol) in THF (40 mL)was then added slowly at 0° C. After addition, the resulting mixture wasallowed to warm to room temperature and stirred for one hr. The reactionsolution was then slowly poured into a 1 N HCl solution (280 mL) and theresulting mixture was diluted with EtOAc (250 mL). The aqueous layer wasextracted with EtOAc (150 mL×3) and the combined organic layers werethen washed with saturated NaHCO₃ (aq), 0.5 M Na₂S₂O₃ (aq) and brine.This organic solution was dried over MgSO₄, filtered and concentratedunder reduced pressure to give the crude product. Purification by flashchromatography on silica gel (Petroleum ether:EtOAc 4:1) gave thedesired product 40 as a colorless oil in quantitative yield. HPLC t_(R)5.24 min.

Example 40 Synthesis of Compound 41 (S)-1-mesyloxy-2-phenylbutane

To a mixture of 40 (3.9 g, 26.0 mmol) and triethylamine (5.5 mL, 39.5mmol) in DCM (90 mL) was added a solution of methanesulfonyl chloride(4.47 g, 39.0 mmol) in DCM (30 mL) slowly at 0° C. After addition, theresulting mixture was allowed to warm to room temperature and stirredfor 2 hrs. 1 N HCl (70 mL) was then added to the above mixture and theaqueous layer was extracted with DCM (1×70 mL). The combined organiclayers were washed with brine (150 mL), dried over MgSO₄, filtered andconcentrated under reduced pressure to give the crude product 41 as acolorless oil. This crude product was used in the next step withoutfurther purification. HPLC t_(R) 6.48 min.

Example 41 Synthesis of Compound 42 (S)-1-azido-2-phenylbutane

A suspension of 41 (5.93 g, 26.0 mmol) and sodium azide (5.7 g, 78.0mmol) in DMF (60 mL) was heated at 85° C. for 3 hrs. After cooling toroom temperature, the mixture was diluted with H₂O (200 mL) andextracted with EtOAc (250 mL). The organic layer was then washed withH₂O (4×150 mL) followed by brine (150 mL), dried over MgSO₄, filteredand concentrated under reduced pressure to give the crude product.Purification by flash chromatography on silica gel (100% petroleum etheras the eluent) gave the pure product 42 (4.03 g, 88%) as a colorlessoil. HPLC t_(R) 7.67 min.

Example 42 Synthesis of Compound 43 (S)-2-phenylbutylamine

A mixture of 42 (4.0 g, 22.8 mmol) and Lindlar's catalyst (1.5 g) inEtOAc (50 mL) was shaken at room temperature under H₂ (40 psi)over-night. The mixture was then filtered through a pad of Celite andthe filtrate was concentrated under reduced pressure to give the crudeproduct 43 (3.4 g, 100%) as a light yellowish oil. This crude productwas used for the conjugate addition reactions without furtherpurification. MS (ESI) 150 (M+1); HPLC t_(R) 1.84 min.

Example 43 Synthesis of Compound 44 allyl2-(methoxy(methyl)amino)-2-oxoethylcarbamate

To Alloc-glycine (1.45 g, 9.1 mmol) in DCM (20 mL) was added BOP reagent(3.3 g, 7.46 mmol) and DIPEA (1.5 mL, 10.7 mmol). After stirring at roomtemperature for 10 mins, N,O-dimethylhydroxylamine hydrochloride (0.8 g,8.2 mmol) and DIPEA (1.5 mL, 10.7 mmol) were added. The reaction wasstirred at room temperature overnight. The DCM was removed by rotaryevaporation and the residue taken up in EtOAc (100 mL). The organicphase was washed with H₂O (3×100 mL), saturated sodium bicarbonatesolution (3×50 mL), H₂O (3×50 mL), 1M hydrochloric acid (3×50 mL), brine(3×50 mL). The organic phase was dried (MgSO₄) and the EtOAc removed togive the Weinreb amide 44 as a white solid (0.43 g, 23%).

Alternatively, tert-butyl 2-(methoxy(methyl)amino)-2-oxoethylcarbamate16 (Boc-Gly Weinreb amide, 1.4 g, 6.4 mmol) in DCM (5 mL) and TFA (3 mL)were stirred at room temperature 1 hr. The solvent was removed underreduced pressure, followed by addition of DCM (20 mL) and then DIPEAuntil basic. The solution was cooled to 0° C. and allyl chloroformateadded (1.4 mL, 13.2 mmol). The reaction was stirred at room temperatureovernight. The reaction mixture was neutralised with 1M hydrochloricacid and extracted with EtOAc. The EtOAc was removed by rotaryevaporation and the residue was subjected to column chromatography onsilica gel using petroleum ether:EtOAc (1:1 to 0:1), providing 44 (0.86g, 66%).

Example 44 Synthesis of Compound 45 allyl 2-oxobut-3-enylcarbamate

To the Weinreb amide 44 (0.43 g, 2.1 mmol) in DCM (5 mL) at 0° C. wasadded vinyl magnesium bromide (10 mmol) in THF (10 mL). The reaction wasstirred for 2 hrs and monitored by HPLC. The reaction was added to amixture of ice and 1M hydrochloric acid (100 mL). The aqueous mixturewas extracted with DCM (3×50 mL) and washed with 1M hydrochloric acid(2×100 mL) and H₂O (3×50 mL). The organic phase was dried (MgSO₄) andthe volume reduced to 50 mL by rotary evaporation. The α,β-unsaturatedketone 45 was stored and used in solution without further purification.

Example 45 Synthesis of Compound 46 (S)-9-fluorenylmethyl10-(3,5-dichlorobenzyl)-2,2-dimethyl-4,9,13,16-tetraoxo-3,17-dioxa-5,10,15-triazaiscos-19-en-8-ylcarbamate

To 3,5-dichlorobenzylamine (0.49 g, 2.8 mmol) in DCM (5 mL) was addedthe α,β-unsaturated ketone 45 (2.12 mmol) in DCM (10 mL). After stirringat room temperature for 15 mins, Fmoc-diaminobutyric acid(Boc)-OH (1.35g, 3.1 mmol) and DIC (0.5 mL, 3.2 mmol) was added. The reaction wasstirred at room temperature overnight. The DCM was removed by rotaryevaporation and the residue was subjected to column chromatography onsilica gel using petroleum ether:EtOAc (1:1 to 0:1), providing compound46 (0.48 g, 22%).

Example 46 Synthesis of Compound 47(3S,5S)-3-(2-tert-butoxycarbonylaminoethyl)-5-(allyloxycarbonylaminomethyl)-1-(3,5-dichlorobenzyl)-1,4-diazepan-2-one

To Compound 46 (0.48 g, 0.63 mmol) in DCM (3 mL) was added diethylamine(1.5 mL). The reaction was stirred at room temperature for 1 hr. The DCMand diethylamine was removed by rotary evaporation. DCM (5 mL), sodiumtriacetoxyborohydride (0.2 g, 0.94 mmol) was added, and the reaction wasstirred overnight at room temperature. The organic phase was washed withsaturated sodium bicarbonate solution (25 mL), dried (MgSO₄) and the DCMremoved to give the cyclised product 47 (0.24 g, 72%).

Example 47 Synthesis of Compound 48(3S,5S)-3-(2-tert-butoxycarbonylaminoethyl)-5-aminomethyl-1-(3,5-dichlorobenzyl)-1,4-diazepan-2-one

To the cyclised product 47 (0.24 g, 0.45 mmol) in DCM (3 mL) was added1,3-dimethylbarbituric acid (13 mg, 0.08 mmol) and palladium tetrakistriphenylphosphine (5 mg). The reaction was evacuated and stirred androom temperature for 1 hr. The DCM was removed under reduced pressure togive the crude product 48 (0.15 g. 75%) which was used in the nextreaction without purification.

Example 48 Synthesis of Compound 49(3S,5S)-3-(2-aminoethyl)-5-(2-naphthoylaminomethyl)-1-(3,5-dichlorobenzyl)-1,4-diazepan-2-one

To the amine 48 (0.05 mg, 0.11 mmol) in DCM (1 mL) was added DIPEA (0.1mL, 0.7 mmol), BOP reagent (0.05 mg, 0.11 mmol) and 2-naphthoic acid(0.04 mg, 0.23 mmol). The reaction was stirred at room temperature for 2hrs. TFA (1 mL) was added and the reaction stirred at room temperaturefor 2 hrs. Rotary evaporation and preparative HPLC gave 49 (48 mg, 90%).MS (ESI) 499.3 (M+1); HPLC t_(R) 5.77 min

Example 49 Synthesis of Compound 50N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthalene-2-sulfonamide

Prepared from allyl 2-oxobut-3-enylcarbamate 45, Boc-L-Arg(Fmoc)₂-OH and2,2-diphenylethylamine according the procedures of Examples 46-48, withthe following modification: the Boc group was removed with TFA duringthe deprotection/cyclization procedure of Example 47, rather thane usingdiethylamine for Fmoc removal. Following Alloc deprotection by theprocedure of Example 48, the free amine was dissolved in DCM to whichwas added naphthalene-2-sulfonyl chloride (10 mg) and DIPEA (20 μL) andthe reaction stirred for 2 h at room temperature. Diethylamine (1 mL)was added and stirred overnight to remove the Fmoc protection, and thereaction evaporated to dryness. Preparative HPLC gave title compound 50(13 mg). MS (ESI) 613.5 (M+1). t_(R) 5.89 min.

Example 50 Synthesis of Compound 51 (S)-9-fluorenylmethyl10-(2-ethylbutyl)-2,2-dimethyl-18-phenyl-4,9,13,16-tetraoxo-3,17-dioxa-5,10,15-triazaoctadecan-8-ylcarbamate

To 2-ethylbutylamine (0.15 g, 1.48 mmol) in DCM (10 mL) was added theα,β-unsaturated ketone 27 (1.47 mmol) in DCM (30 mL). After stirring atroom temperature for 15 mins, Fmoc-diaminobutyric acid(Boc)-OH (0.95 g,2.16 mmol) and DIC (0.34 mL, 2.19 mmol) were added. The reaction wasstirred at room temperature overnight. The DCM was removed by rotaryevaporation and the residue was subjected to column chromatography onsilica gel using petroleum ether:EtOAc (1:1 to 0:1), providing Compound51 (0.5 g, 46%).

Example 51 Synthesis of Compound 52(3S,5S)-3-(2-tert-butoxycarbonylaminoethyl)-5-(benzyloxycarbonylaminomethyl)-1-(2-ethylbutyl)-1,4-diazepan-2-one

To Compound 51 (0.5 g, 0.67 mmol) in DCM (3 mL) was added diethylamine(1.5 mL). The reaction was stirred at room temperature for 1 hr. The DCMand diethylamine were removed by rotary evaporation. DCM (5 mL) andsodium triacetoxyborohydride (0.2 g, 0.94 mmol) were added and thereaction was stirred overnight at room temperature. The organic phasewas washed with saturated sodium bicarbonate solution (25 mL), dried(MgSO₄) and the DCM removed to give the crude cyclised product 52 (0.4g).

Example 52 Synthesis of Compound 53(3S,5S)-3-(2-tert-butoxycarbonylaminoethyl)-5-(aminomethyl)-1-(2-ethylbutyl)-1,4-diazepan-2-one

To the cyclised product 52 (0.4 g) in methanol (5 mL) was addedcatalytic Pd/C. The reaction was stirred under a hydrogen atmosphereovernight. The reaction mixture was filtered through Celite and themethanol removed by rotary evaporation to give the amine 53 (0.17 g, 68%from 51).

Example 53 Synthesis of Compound 54N-(((3S,5S)-3-(2-aminoethyl)-1-(2-ethylbutyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide

To the amine 53 (0.030 g, 0.08 mmol) in DCM (1 mL) was added DIPEA (0.1mL, 0.7 mmol), BOP reagent (0.03 g, 0.07 mmol) and 2-naphthoic acid(0.025 g, 0.14 mmol). The reaction was stirred at room temperature for 2hrs. TFA (1 mL) was added and the reaction stirred at room temperaturefor 2 hrs. Rotary evaporation and preparative HPLC gave Compound 54 (23mg, 68%). MS (ESI) 425.7 (M+1); HPLC t_(R) 5.27

Example 54 Synthesis of Compound 55(3S,5S)-3-[2-(piperidin-1-yl)ethyl]-5-(benzyloxycarbonylaminomethyl)-1-(2-ethylbutyl)-1,4-diazepan-2-one

To Compound 54 (0.25 g, 0.5 mmol) in DCM (3 mL) was added TFA (1.5 mL),with the solution stirred at room temperature for 1 hr. DCM (20 mL) wasadded and the solution was washed with saturated sodium bicarbonatesolution (20 mL), dried over MgSO₄ and evaporated to give the crudeamine (0.16 g). To this was added DMF (0.25 mL), potassium carbonate (10mg) and 1,5-dibromopentane (0.35 mL, 2.5 mmol). The reaction mixture wasstirred at room temperature for 1.5 hrs, after which DCM (20 mL) wasadded, the organic layer washed with saturated sodium bicarbonatesolution (20 mL) and H₂O (20 mL), dried (MgSO₄) and evaporated to givecrude 55, which was used in the next reaction without purification.

Example 55 Synthesis of Compound 56(3S,5S)-3-[2-(piperidin-1-yl)ethyl]-5-aminomethyl-1-(2-ethylbutyl)-1,4-diazepan-2-one

To the cyclised product 55 (0.4 g) in methanol (5 mL) was addedcatalytic Pd/C. The reaction was stirred under a hydrogen atmosphereovernight. The reaction mixture was filtered through Celite and themethanol removed by rotary evaporation to give the amine 56 (0.12 g).

Example 56 Synthesis of Compound 57 2-ethyl-3-methylbutan-1-amine

A solution of 3,3-dimethylacrylic acid (2.00 g, 20 mmol) in THF (30 mL)was added dropwise to a solution of LDA (44 mmol) in THF/hexane (60 mL)at −78° C. After warming to −10° C. and stirring for 20 min, thereaction was recooled to −78° C. and a solution of ethyl iodide (6.86 g,44 mmol)) in THF (30 mL) was added. The reaction was allowed to warm toroom temperature overnight. To the resulting dark orange solution wasadded 1M HCl until acidic. The organic layer was separated, washed withH₂O and brine, dried (MgSO₄), filtered and concentrated to yield a brownoil of 2-ethyl-3-methylbut-3-enoic acid (3.08 g), which was used crudein the next reaction. To reduce the acid group the crude product wasdissolved in THF (70 mL) and cooled to 0° C. To this was added LiAlH₄(2280 mg, 60 mmol). Workup gave 2.7 g of a pale yellow oil, which waspurified by flash chromatography (silica gel, 10% EtOAC in pet. ether)to give 1.70 g of 2-ethyl-3-methylbut-3-en-1-ol as an oil. The alcohol(560 mg, 4.91 mmol) was converted into a mesylate by dissolving in DCM(25 mL) at 0° C., then adding MsCl (675 mg, 5.9 mmol) followed by Et₃N(595 mg, 5.9 mmol). After 30 min the reaction was partitioned betweenDCM and 0.1 N HCl, the aqueous layer extracted with DCM (2×), and theorganic fractions combined and washed with brine, filtered andconcentrated to give 200 mg of a pale yellow oil. The crude mesylate(4.91 mmol) was dissolved in acetonitrile (20 mL) and NaN₃ (957 mg, 14.7mmol) was added. After 1 h DMF (6.5 mL) was added and the reactionheated to reflux for 3 h, then cooled. EtOAc (40 mL) and NaHCO₃ solutionwere added and the organic layer was washed with H₂O (2×), brine (1×)and dried, then filtered to give a pale yellow solution of3-(azidomethyl)-2-methylpent-1-ene that was used crude in the nextreaction. A suspension of the azide (4.91 mmol) in 50 mL EtOAC washydrogenated at 40 psi over Lindlar catalyst (460 mg) for 16 h, thenfiltered through Celite to leave a colourless solution. Flashchromatography (silica gel, 1-5% MeOH in DCM) produced 120 mg of pureamine 57, with a further 95 mg of impure material

Example 57 Synthesis of Compound 58(3S,5S)-3-(2-tert-butoxycarbonylaminopropyl)-5-[benzyloxycarbonyl(methylamino)methyl]-1-(2,2diphenylethyl)-1,4-diazepan-2-one

Prepared from Cbz-Sar, 2,2-diphenylethylamine and Fmoc-L-Orn(Boc)according to the procedures of Examples 26-29.

Example 58 Synthesis of Compound 59(3S,5S)-3-(2-tert-butoxycarbonylaminopropyl)-5-(methylamino)methyl-1-(2,2-diphenylethyl)-1,4diazepan-2-one

The cyclised product 58 (1.9 g) was dissolved in methanol (10 mL) withcatalytic Pd/C and hydrogenated under a hydrogen atmosphere (40 psi)overnight. The reaction mixture was filtered through Celite and themethanol removed by rotary evaporation to give the amine 59 (1.86 g,97%).

Example 59 Synthesis of Compound 60N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-6-bromo-N-methyl-2-naphthamide

The amine 59 was coupled with 6-bromo-2-naphthoic acid then deprotectedwith TFA according to Example 31. Rotary evaporation and preparativeHPLC gave 60 (7.8 mg). MS (ESI) 629.4 (M+1). t_(R) 6.27 min.

Example 60 Synthesis of Compound 61(3S,5S)-3-(tert-butoxycarbonylaminopropyl)-5-(6-bromo-2-naphthamidomethyl)-1-(2,2-diphenylethyl)-1,4-diazepan-2-one

Prepared from 2,2-diphenylethylamine, Fmoc-L-Orn(Boc) and6-bromo-2-naphthoic acid according to the procedures of Examples 29-32,without the TFA deprotection step of Example 31.

Example 61 Synthesis of Compound 62N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylethyl)-4-methyl-2-oxo-1,4-diazepan-5-yl)methyl)-6-bromo-2-naphthamide

Compound 61 (20.8 mg) was dissolved in DMF (1 mL) and treated withmethyl iodide (6 μL) at room temperature for 1 week. Additional methyliodide (0.5 mL) and K₂CO₃ were added and the reaction left at roomtemperature for an additional 2 days. TFA (2 mL) was added and thereaction stirred at room temperature for 2 h. Rotary evaporationfollowed by evaporation under high vacuum then preparative HPLC gave 62(8.5 mg). MS (ESI) 629.3 (M+1); HPLC t_(R) 6.22 min.

Example 62 Synthesis of Compound 63N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2-diphenylethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide

Obtained from 9, 2,2-diphenylethylamine and Fmoc-L-Orn(Boc) according toExamples 10-12. The Boc group was removed under standard conditions togive the free amine. MS (ESI) 535 (M+1); HPLC t_(R) 5.78 min

Example 63 Synthesis of Compound 64N-(((3S,5S)-1-(2,2-diphenylethyl)-2-oxo-3-(3-(piperidin-1-yl)propyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide

The amine 63 (0.79 g, 1.48 mmol), 1,5-dibromopentane (0.2 mL, 1.48 mmol)and K₂CO₃ (0.79 g) in DMF (11 mL) was stirred at room temperature for 4h. The resulting mixture was diluted with ethylacetate (30 mL), washedwith H₂O (5×30 mL), brine (10 mL) and dried over MgSO₄. Purification bypreparative HPLC yielded 64 (0.23 g, 25%). MS (ESI) 603.3 (M+1); HPLCt_(R) 6.04 min

Example 64 Synthesis of Compound 65N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-(isopropylamino)propyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide

To a stirred mixture of the amine 63 (11 mg, 0.02 mmol), acetone (2 mL)and MgSO₄ (50 mg) in DCM (5 mL) was added sodium triacetoxyborohydride(8.5 mg, 0.04 mmol) at room temperature. Stirring continued for 2 h, themixture was concentrated, re-dissolved in EtOAc (5 mL), washed withsaturated aqueous NaHCO₃ solution (10 mL) and brine (10 mL), dried overMgSO₄ and concentrated under reduced pressure. Purification bypreparative HPLC yielded 65 (9.5 mg, 80%). MS (ESI) 577.2 (M+1); HPLCt_(R) 5.97 min.

Example 65 Synthesis of Compound 66 tert-butyl(methylamino)(methylthio)methylenecarbamate

DIAD (2.7 mL, 13.8 mmol) was added to a stirred mixture ofthiopseudourea (2.0 g, 6.9 mmol), PPh₃ (3.6 g, 13.8 mmol), and MeOH(0.55 mL, 13.8 mmol) in dry THF (5 mL) at 0° C. under nitrogen. Stirringcontinued at 0° C. for 3 h then at room temperature for 16 h. Thesolvent was removed under reduced pressure and the resulting residue wasre-dissolved in EtOAc, washed with saturated aqueous NaHCO₃ solution (20mL) and brine (20 mL), and dried over MgSO₄. Purification by silica gelchromatography using 20% EtOAc in petroleum ether as eluent gave 66(1.63 g, 78%) as a colourless oil. MS (ESI) 305 (M+1); HPLC t_(R) 7.97min.

Example 66 Synthesis of Compound 67N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-(3-methylguanidino)propyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide

A mixture of Compound 63 (10 mg, 0.019 mmol), guanylating agent 66 (56.9mg, 0.19 mmol) and DIPEA (6.6 μL, 0.038 mmol) in DCM (5 mL) was stirredat room temperature for 16 h. TFA (5 mL) was added, and the resultingmixture was stirred at room temperature for 30 min. Solvent was removedunder reduced pressure, and the crude product was purified bypreparative HPLC to give 67 (0.53 mg, 4.7%) as a white solid. MS (ESI)591.3 (M+1); HPLC t_(R) 5.94 min

Example 67 Synthesis of Compound 68 (S)-9-fluorenylmethyl1-phenyl-10-(2,2-diphenylethyl)-18,18-dimethyl-4,9,13,16-tetraoxo-2,17-dioxa-4,10,15-triazanonadecan-8-ylcarbamate

To a stirred mixture of Fmoc-L-Orn(Cbz)-OH (1.78 g, 3.65 mmol), DIPEA(0.64 mL, 3.65 mmol) and HATU (1.39 g, 3.65 mmol) in DCM (10 mL) wasadded a solution of amine 17 at room temperature. Stirring continued for3 h, the reaction mixture was washed with saturated NaHCO₃ aqueoussolution (20 mL) and brine (20 mL), and dried over MgSO₄. The solventwas removed under reduced pressure, with the crude 68 used in the nextstep without further purification. MS (ESI) 853 (M+1); HPLC t_(R) 9.90min.

Example 68 Synthesis of Compound 69 (S)-(9H-fluoren-9-yl)methyl7-((4-(tert-butoxycarbonylamino)-3-oxobutyl)(2,2-diphenylethyl)carbamoyl)-3-methyl-1,3-diazepane-1-carboxylate

A mixture of 68 (136 mg, 0.159 mmol) and Pd/C (20 mg) in ethanol (5 mL)was shaken under H₂ at 30 psi for 16 h, then filtered, concentratedunder reduced pressure to give the crude amine (90 mg, 78%). The amine(90 mg, 0.125 mmol) was treated with excess formaldehyde solution in H₂O(37 mmol) in MeOH (5 mL) followed by sodium triacetoxyborohydride (23.5mg, 0.375 mmol). After 1 h, the reaction mixture was washed withsaturated NaHCO₃ aqueous solution (10 mL) and brine (10 mL), dried overMgSO₄, filtered and concentrated. The crude material was used in thenext step without further purification. MS (ESI) 745 (M+1); HPLC t_(R)7.83 min.

Example 69 Synthesis of Compound 70 (S)-(9H-fluoren-9-yl)methyl7-((4-(2-naphthamido)-3-oxobutyl)(2,2-diphenylethyl)-carbamoyl)-3-methyl-1,3-diazepane-1-carboxylate

Compound 69 (8 mg, 0.011 mmol) was treated with 1:1 v/v trifluoraceticacid/DCM mixture (2 mL) for 30 min at room temperature. The mixture wasconcentrated under reduced pressure, re-dissolved in DCM (5 mL), washedwith saturated NaHCO₃ aqueous solution (5 mL) and brine (5 mL), driedover MgSO₄ and filtered. The filtrate was then treated with a mixture of2-naphthoic acid (1.8 mg, 0.011 mmol), DIPEA (5.7 μL, 0.033 mmol) andBOP (4.8 mg, 0.011 mmol) in DCM (1 mL) with stirring at roomtemperature. After 3 h, the reaction mixture was washed with saturatedNaHCO₃ aqueous solution (10 mL) and brine (10 mL), dried over MgSO₄,filtered and concentrated. The crude material was used in the next stepwithout further purification. MS (ESI) 799 (M+1); HPLC t_(R) 7.90 min.

Example 70 Synthesis of Compound 71N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-(methylamino)propyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide

To a stirred solution of 70 (0.011 mmol) in DCM (5 mL) was addeddiethylamine (5 mL) at room temperature. The reaction was stirred for 1h, then concentrated under reduced pressure. The residue wasre-dissolved in DCM (5 mL) followed by addition sodiumtriacetoxyborohydride (5 mg, 0.08 mmol) at room temperature. Stirringcontinued for 1 h, with the resulting mixture washed with saturatedNaHCO₃ aqueous solution (10 mL) and brine (10 mL), dried over MgSO₄,filtered and concentrated. Purification by preparative HPLC yielded 71(0.21 mg) as a white solid. MS (ESI) 549.3 (M+1); HPLC t_(R) 5.93 min

Example 71 Synthesis of Compound 72(S)-2-(allyloxycarbonylamino)-3-(naphthalen-2-yl)propanoic acid

To a stirred mixture of L-3-(2-naphthyl)alanine hydrochloride (5.0 g,19.8 mmol), Na₂CO₃ (7.3 g, 69.3 mmol) and 1,4-dioxane (30 mL) in H₂O (50mL) was added allylchloroformate (2.1 mL, 19.8 mmol) at 0° C. Theresulting mixture was stirred for 16 h then concentrated under reducedpressure. The residue was diluted with ethylacetate (50 mL), and at 0°C. acidified to pH 2. The aqueous phase was extracted with ethylacetate(3×20 mL), the combined organic phase was washed with H₂O (50 mL) andbrine (20 mL), dried over MgSO₄, filtered and concentrated under reducedpressure to give 72 as a colourless oil (5.8 g, 97%), which was used inthe next step without further purification. HPLC t_(R) 6.60 min.

Example 72 Synthesis of Compound 73 (S)-allyl1-(methoxy(methyl)amino)-3-(naphthalen-2-yl)-1-oxopropan-2-ylcarbamate

To a stirred mixture of the acid 72 (5.84 g, 19.5 mmol), DIPEA (3.7 mL,2.09 mmol) and BOP (8.63 g, 19.5 mmol) in DCM (10 mL) was added apre-mixed solution of N,O-dimethylhydroxylamine hydrochloride (1.9 g,19.5 mmol) and DIPEA (7.3 mL, 41.6 mmol) in DCM (10 mL) at roomtemperature. Stirring continued for 16 h the reaction mixture was washedwith 1N HCl (3×60 mL), H₂O (3×60 mL), saturated NaHCO₃ aqueous solution(3×60 mL) and brine (60 mL), dried over MgSO₄. Purification by silicagel chromatography using 20% ethylacetate in petroleum ether as eluentgave 73 (4.83 g, 71%) as a colourless oil. MS (ESI) 343 (M+1); HPLCt_(R) 7.07 min.

Example 73 Synthesis of Compound 74 (S)-allyl1-(naphthalen-2-yl)-3-oxopent-4-en-2-ylcarbamate

At 0° C. a solution of vinylmagnesium bromide in THF (11.5 mL, 1 M) wasadded in one portion to Weinreb amide 73 (1.58 g, 4.62 mmol) undernitrogen with stirring. The resulting mixture was allowed to stir for 2h, and poured into a 1N HCl/ice mixture (50 mL). The aqueous mixture wasextracted with DCM (3×20 mL), the combined DCM extract was washed with1N HCl (50 mL), saturated NaHCO₃ aqueous solution (50 mL) and brine (20mL), dried over MgSO₄. Solvent was removed under reduced pressureproducing the product 74 (1.14 g, 80%), which was used in the next stepwithout further purification. MS (ESI) 310 (M+1); HPLC t_(R) 7.51 min.

Example 74 Synthesis of Compound 75 (S)-allyl5-(2,2-diphenylethylamino)-1-(naphthalen-2-yl)-3-oxopentan-2-ylcarbamate

To a stirred solution of 2,2-diphenylethylamine (0.45 g, 2.3 mmol) inDCM (55 mL) was added the vinyl ketone 74 (0.71 g, 2.3 mmol) in oneportion. Stirring continued for 2 h, with the reaction mixture used inthe next step without purification. MS (ESI) 507 (M+1); HPLC t_(R) 7.22min.

Example 75 Synthesis of Compound 76 (S)-allyl 5-(N-(Boc-L-Arg(Cbz)₂)2,2-diphenylethylamino)-1-(naphthalen-2-yl)-3-oxopentan-2-ylcarbamate

To a stirred solution of the amine adduct 75 (2.3 mmol) was added amixture of Boc-Arg(Cbz)₂-OH (1.25 g, 2.3 mmol), DIPEA (0.8 mL, 4.6 mmol)and HATU (0.87 g, 2.3 mmol) in DCM (15 mL) at room temperature. Stirringcontinued for 16 h, after which the reaction mixture was washed withsaturated NaHCO₃ aqueous solution (3×20 mL) and brine (10 mL) then driedover MgSO₄. Purification by silica gel chromatography using 20%ethylacetate in petroleum ether as eluent gave 76 as a colourless oil(708 mg, 30% over 3 steps). MS (ESI) 1031 (M+1); HPLC t_(R) 10.80 min.

Example 76 Synthesis of Compound 77 allyl(S)-1-((3S,5RS)-1-(2,2-diphenylethyl)-3-(bis Cbz3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)-2-(naphthalen-2-yl)ethylcarbamate

To a stirred solution of acyclic intermediate 76 (0.48 g, 0.47 mmol) inDCM (5 mL) was added TFA (5 mL) at room temperature. Stirring continuedfor 30 min, after which the mixture was diluted with DCM (20 mL) thenwashed with saturated NaHCO₃ aqueous solution (3×20 mL) and brine (10mL), and dried over MgSO₄. To the resulting solution was added sodiumtriacetoxyborohydride (0.2 g, 0.94 mmol) with stirring at roomtemperature, after 30 min the mixture was washed with saturated NaHCO₃aqueous solution (3×20 mL) and brine (10 mL), then dried over MgSO₄. Thecrude 77, a mixture of diastereomers at the diazepan-2-one C5, was usedin the next step without further purification. MS (ESI) 915 (M+1)

Example 77 Synthesis of Compound 78 bis(Cbz)1-(3-((2S,7RS)-7-((S)-1-amino-2-(naphthalen-2-yl)ethyl)-4-(2,2-diphenylethyl)-3-oxo-1,4-diazepan-2-yl)propyl)guanidine

A mixture of compound 77 (36 mg, 0.039 mmol), 1,3-dimethylbarbituricacid (7.4 mg, 0.047 mmol) and Pd(PPh₃)₄ in DCM (5 mL) was stirred atroom temperature under vacuum for 4 h. The resulting mixture was used inthe next step without further purification. MS (ESI) 832 (M+1)

Example 78 Synthesis of Compounds 79 and 80N—((S)-1-((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)-2-(naphthalen-2-yl)ethyl)acetamideandN—((S)-1-((3S,5R)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)-2-(naphthalen-2-yl)ethyl)acetamide

A solution of the amine 78 (0.09 mmol) in DCM (5 mL) was treated withacetic anhydride (8.6 μL, 0.09 mmol) with stirring at room temperature.After 3 h the mixture was concentrated, re-dissolved in EtOAc, washedwith saturated NaHCO₃ aqueous solution (10 mL) and brine (10 mL), driedover MgSO₄, then concentrated under reduced pressure. The residue wasdissolved in MeOH (10 mL), Pd/C (5 mg) was added, and the solutionshaken under H₂ at 20 psi for 16 h. The reaction was filtered,concentrated and purified by preparative HPLC to give the preferreddiastereomer 79 (3 mg) and the less preferred diastereomer 80 (6 mg) aswhite solids.

79: MS (ESI) 606.4 (M+1); HPLC t_(R) 6.033 min

80: MS (ESI) 606.3 (M+1); HPLC t_(R) 6.046 min

Example 79 Synthesis of Compounds 81 and 82(S)-2-acetamido-N-((S)-1-((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)-2-(naphthalen-2-yl)ethyl)-3-(1H-imidazol-5-yl)propanamideand(S)-2-acetamido-N-((S)-1-((3S,5R)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)-2-(naphthalen-2-yl)ethyl)-3-(1H-imidazol-5-yl)propanamide

To a stirred mixture of Ac-L-His-OH (33.6 mg, 0.156 mmol), DIPEA (112.5μL, 0.312 mmol) and BOP (68.8 mg, 0.156 mmol) in DMF (1 mL) was addedthe amine 78 (0.039 mmol) at room temperature. Stirring continued for 16h, then the reaction mixture was diluted with DCM/H₂O mixture (10 mL,1:1 v/v), and the aqueous phase was extracted with DCM (3×5 mL). Thecombined DCM extracts were washed with saturated NaHCO₃ aqueous solution(3×20 mL) and brine (10 mL), dried over MgSO₄, and concentrated underreduced pressure. The residue was re-dissolved in MeOH (5 mL), and Pd/C(20 mg) was added. The resulting mixture was shaken under H₂ at 30 psifor 16 h, then was filtered, concentrated and purified by preparativeHPLC to give the preferred diastereomer 81 (1.9 mg) and the lesspreferred diastereomer 82 (0.9 mg) as white solids.

81: MS (ESI) 743.4 (M+1); HPLC t_(R) 5.489 min

82: MS (ESI) 743.4 (M+1); HPLC t_(R) 5.555 min

Example 80 Synthesis of Compounds 83 and 84 propyl(S)-1-((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)-2-(naphthalen-2-yl)ethylcarbamateand propyl(S)-1-((3S,5R)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)-2-(naphthalen-2-yl)ethylcarbamate

A mixture of 77 (36 mg, 0.039 mmol) and Pd/C (5 mg) in MeOH (5 mL) wasshaken under H₂ at 20 psi for 16 h, then was filtered, concentrated andpurified by preparative HPLC to give the preferred diastereomer 83 (0.07mg) and the less preferred diastereomer 84 (2.7 mg) as white solids.

83: MS (ESI) 650.3 (M+1); HPLC t_(R) 6.52 min

84: MS (ESI) 650.2 (M+1); HPLC t_(R) 6.64 min

Example 81 Synthesis of Compounds 85-871-(3-((2S,7S)-7-(N—R1(R)-1-amino-2-(naphthalen-2-yl)ethyl)-4-(2,2-diphenylethyl)-3-oxo-1,4-diazepan-2-yl)propyl)guanidine

Compounds 85-87 were prepared in the same fashion as the preferreddiastereomers Compounds 79, 81 and 83 using the procedures described inExamples 71-80 with D-(2-naphthyl)alanine hydrochloride as the startingmaterial.

Compound R₁ group MS (M + 1) t_(R) (min) 85 Ac 606.2 6.01 86 Ac-His743.5 5.41 87 Propyloxycarbonyl 650.4 6.42

Examples 82-90 Synthesis Via Scheme 2: Preparation of all FourDiastereomers ofN-((1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide88

Example 82 Synthesis of Compound 892,2-dimethyl-10-(2,2-diphenylethyl)-4,7,11-trioxo-3,12-dioxa-5,10-diazapentadec-14-ene

2,2-Diphenylethylamine (3 g) was added to Boc-vinylketone 16 (2.8 g) asin Example 18. To the crude adduct 17 was added Alloc-Cl (1.6 mL) andthe reaction stirred until TLC indicated consumption of the secondaryamine. THE solvent was evaporated and the residue purified by columnchromatography (SiO₂ gel, pet. ether/EtOAc) to give 3.2 g (57%) of 89.

Example 83 Synthesis of Compound 90 (S)-allyl2-amino-5-(benzyloxycarbonylamino)pentanoate L-H-Orn(Cbz)-Oallyl

H-L-Orn(Cbz)-OH (6.66 g, 25 mmol), allyl alcohol (17.56 mL, 25 mmol) andp-TsOH (5.7 g, 30 mmol) were dissolved in benzene (200 mL) and refluxedunder Dean-Stark conditions for 5 h. The majority of the solvent wasthen distilled off, with the remainder removed under vacuum. Theresulting solid was recrystallized from DCM, filtered and dried to give11.19 g (94%) of the tosylate salt. To obtain the free amine the solidwas dissolved in DCM, washed with sat. NaHCO₃, the aqueous layer washedwith DCM (3×), and the organic layers dried over MgSO₄ and evaporated todryness.

Example 84 Synthesis of Compound 91 (R)-allyl2-amino-5-(benzyloxycarbonylamino)pentanoate D-H-Orn(Cbz)-Oallyl

H-D-Orn(Cbz)-OH (6.66 g, 25 mmol) was converted into 10.93 g (91%) ofthe tosylate salt of 91 as in Example 83, then converted into the freeamine.

Example 85 Synthesis of Compound 92 (2R)-allyl5-(benzyloxycarbonylamino)-2-(10-(2,2-diphenylethyl)-2,2-dimethyl-4,11-dioxo-3,12-dioxa-5,10-diazapentadec-14-en-7-ylamino)pentanoate

The protected aminoketone 89 (746 mg, 1.6 mmol), D-Orn(Cbz)-Oallyl 91(538 mg, 1.76 mmol) and NaBH(OAc)₃ (678 mg, 3.2 mmol) in a minimumvolume of DCM were stirred for 24 h. A drop of AcOH was added justbefore workup, at which point saturated NaHCO₃ was added, extracted withDCM (3×), and the organic extracts combined and washed with saturatedNaHCO₃ and H₂O, dried over MgSO₄, and evaporated to dryness. The productwas purified by column chromatography (SiO₂ gel, pet. ether/EtOAc) togive 890 mg (74%) of 92 as a mixture of diastereoisomers.

Example 86 Synthesis of Compound 93 (2S)-allyl5-(benzyloxycarbonylamino)-2-(10-(2,2-diphenylethyl)-2,2-dimethyl-4,11-dioxo-3,12-dioxa-5,10-diazapentadec-14-en-7-ylamino)pentanoate

L-Orn(Cbz)-Oallyl 90 (592 mg, 1.93 mmol) was converted into a mixture ofthe set of diastereomers 93 (925 mg, 76%) following the procedures ofExample 85.

Example 87 Synthesis of Compounds 94 and 95 (3R,5S)-5-(N-Bocaminomethyl)-3-(N-Cbz3-aminopropyl)-1-(2,2-diphenylethyl)-1,4-diazepan-2-one and(3R,5R)-5-(N-Boc aminomethyl)-3-(N-Cbz3-aminopropyl)-1-(2,2-diphenylethyl)-1,4-diazepan-2-one

The Alloc/allyl protected derivative 92 (840 mg, 1.11 mmol) wasdissolved in a minimum of DCM. 1,3-Dimethylbarbituric acid (346 mg, 2.22mmol) and catalytic Pd(PPh₃)₄ were added, and the reaction degassedunder vacuum, sealed and stirred overnight. The reaction was diluted to50 mL with DCM, DIPEA (430 mg, 3.33 mmol) and BOP (540 mg, 1.22 mmol)were added, and the reaction stirred for 30 min. The DCM was removedunder vacuum and the residue taken up in EtOAc, washed (saturatedNaHCO₃, H₂O, saturated NaCl), dried (MgSO₄) and evaporated to dryness(TLC: EtOAc, 2 spots, R_(f) 0.33 and 0.57). The two diastereomericproducts were separated by column chromatography (SiO₂ gel, pet.ether/EtOAc) to give 362 mg of the earlier eluting (3R,5S) isomer 94,and 342 mg of the later eluting (3R,5R) isomer 95.

Example 88 Synthesis of Compounds 96 and 97 (3S,5R)-5-(N-Bocaminomethyl)-3-(N-Cbz3-aminopropyl)-1-(2,2-diphenylethyl)-1,4-diazepan-2-one and(3S,5S)-5-(N-Boc aminomethyl)-3-(N-Cbz3-aminopropyl)-1-(2,2-diphenylethyl)-1,4-diazepan-2-one

The (3S,5R) (312 mg) and (3S,5S) (331 mg) isomers were obtained from theL-Orn-derived acyclic material 93 (870 mg) following the procedure ofExample 87.

Example 89 Synthesis of Compounds 98-101 5-(N-Bocaminomethyl)-3-(N,N′-Cbz₂3-guanidinopropyl)-1-(2,2-diphenylethyl)-1,4-diazepan-2-one

The Orn Cbz group of 94 was removed by hydrogenation (H₂, 30 psi) overcatalytic Pd/C in methanol overnight. The solution was filtered throughCelite and evaporated to give a solid. A solution of the resulting amine(187 mg, 0.39 mmol) in DCM was mixed with a solution of the guanylatingreagent CbzNHC(═NCbz)NHTf (196 mg, 0.43 mmol) in DCM. Triethylamine(TEA) (43 mg, 0.43 mmol) was added, and the reaction stirred overnight.The solution was diluted with DCM, washed (KHSO₄, sat. NaHCO₃, brine),dried (MgSO₄) and evaporated to dryness, then purified by flashchromatography over SiO₂ using hexanes/EtOAc as eluent, to give (3R,5S)98 (182 mg, 59%). The other isomers 95-97 were converted in a similarmanner to give:

99 (3R,5R): 171 mg (68%) from 148 mg of amine

100 (3S,5S): 80 mg (65%) from 72 mg of amine

101 (3S,5R): 142 mg (58%) from 144 mg of amine

Example 90 Synthesis of Compounds 102-105

-   102    N-(((3R,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide-   103    N-(((3R,5R)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide-   104    N-(((3S,5R)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide-   105    N-(((3S,5S)-1-(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthamide

The Boc derivative 99 (180 mg) in DCM (1 mL) was treated with TFA (1 mL)for 20 mL. The solvent was removed by evaporation, a solution of NaHCO₃was added, and extracted 3× with DCM. The dichloromethane solution wasdried over MgSO₄, filtered and evaporated to dryness. A portion (56 mg,0.086 mmol) of the crude deprotected amine in DCM was stirred with2-naphthoic acid (16 mg), DIPEA (60 μL) and BOP (42 mg) for 30 min. MeOHwas added and the reaction stirred overnight. The reaction was filtered,then purified by flash chromatography over SiO₂ using petroleumether/EtOAc as eluent, to give the (3R,5R) isomer (43 mg, 94%). Theother isomers were converted in a similar manner to give: (3R,5S): 41 mg(85%) from 60 mg 98, (3S,5R): 27 mg (70%) from 40 mg 101 and (3S,5S): 13mg (74%) from 20 mg 100 Each compound was dissolved in dioxane:MeOH andhydrogenated over catalytic Pd/C under 30 psi H₂ overnight. The solutionwas filtered through Celite and evaporated to give a solid.

102 (3R,5S): 27 mg (96%) from 41 mg, 103 (3R,5R): 25 mg (85%) from 43mg, 104 (3S,5R): 11 mg (quantitative) from 13 mg and 105 (3S,5S): 3 mg(73%) from 6 mg

Compound stereochemistry MS (M + 1) t_(R) (min) 102 (3R,5S) 577.4 5.775103 (3R,5R) 577.5 5.750 104 (3S,5R) 577.5 5.783 105 (3S,5S) 577.3 5.787

Example 91 Synthesis of Compounds 406, 526, 541-546

-   406    6-chloro-N-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide-   526    6-chloro-N-(((3S,5S)-2-oxo-1-((R)-2-phenylbutyl)-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide-   541    6-chloro-N-(((3R,5R)-2-oxo-1-((R)-2-phenylbutyl)-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide-   542    6-chloro-N-(((3S,5R)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide-   543    6-chloro-N-(((3R,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide-   544    6-chloro-N-(((3S,5R)-2-oxo-1-((R)-2-phenylbutyl)-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide-   545    6-chloro-N-(((3R,5S)-2-oxo-1-((R)-2-phenylbutyl)-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide-   546    6-chloro-N-(((3R,5R)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide

Compounds 406, 526, and 541-546 were prepared following similarprocedures as used to prepare Compounds 102-104 (Scheme 2 route). Inaddition, compounds 406, 526, 541 and 546 were prepared according to theScheme 1 route; a detailed procedure for the preparation of Compound 406is contained in Examples 92-99.

Compound stereochemistry MS (M + 1) t_(R) (min) 406 (3S,5S,2′S) 575.36.269 526 (3S,5S,2′R) 574.8 6.265 541 (3R,5R,2′R) 575.4 6.404 542(3S,5R,2′S) 575.2 6.262 543 (3R,5S,2′S) 575.2 6.110 544 (3S,5R,2′R)575.1 6.211 545 (3R,5S,2′R) 575.2 6.253 546 (3R,5R,2′S) 575.4 6.274

Example 92 Synthesis of Compound 547(S)—N-(2-oxo-4-(2-phenylbutylamino)butyl)-3-phenylpropanamide

To a solution of (S)-phenylbutylamine (8.5 g, 57.07 mmol) in DCM (100ml) was added a solution of α,β-unsaturated ketone 27 (12.5 g, 57.1mmol) in DCM (100 ml) at room temperature in one portion. The resultingmixture was stirred until all of the α,β-unsaturated ketone had beenconsumed (within one hour), then the conjugate addition adduct 547 wasused straight in the next reaction.

HPLC t_(R) 5.71 min

MS (ESI) 369.3 (M+1)

Example 93 Synthesis of Compound 548 (S)-9-fluorenylmethyl10-[(S)-2-phenylbutyl]-2,2-dimethyl-18-phenyl-4,9,13,16-tetraoxo-3,17-dioxa-5,10,15-triazaoctadecan-8-ylcarbamate

To the freshly prepared amine 547 in DCM (200 mL) was addedFmoc-L-Dab(Boc)OH (32.7 g, 74.2 mmol) followed by DIPC (11.5 g, 74.2mmol) at room temperature. The resulting mixture was stirred for 2hours, the by-product diisopropylurea was removed by filtration througha pad of Celite®, and the filtrate was concentrated under reducedpressure to give the crude product, which was purified by silica gelcolumn chromatography using 30-70% EtOAc/Pet. Spirit as eluent to give548 (19.9 g, 44% yield over two steps).

TLC rf 0.23 (50% EtOAc/Pet. Spirit)

HPLC t_(R) 10.03 min

MS (ESI) 791.2 (M+1)

Example 94 Synthesis of Compound 549(S)-10-[(S)-2-phenylbutyl]-2,2-dimethyl-8-amino-18-phenyl-4,9,13,16-tetraoxo-3,17-dioxa-5,10,15-triazaoctadecane

Diethylamine (30 mL) was added to a solution of the acylated amine 548(19.9 g, 25.19 mmol) in DCM (30 mL) at room temperature and theresulting mixture was stirred for 30 min. The solvent and diethylaminewere removed under reduced pressure to give the desired product 549. Itwas used in the next step without further purification.

HPLC t_(R) 6.85 min

MS (ESI) 569.3 (M+1)

Example 95 Synthesis of Compound 550(3S,5S)-3-(2-tert-butoxycarbonylaminoethyl)-5-(benzyloxycarbonylaminomethyl)-1-[(S)-2-phenylbutyl]-1,4-diazepan-2-one

To a solution of crude Fmoc deprotected material 549 in DCM (50 ml) wasadded AcOH (15 mL) followed by NaBH(OAc)₃ (5.34 g, 25.2 mmol) in oneportion at room temperature. The resulting mixture was stirred for 30min, then washed with saturated NaHCO₃(aq) solution (80 mL×3), brine (80mL) and dried over MgSO₄. Filtration and concentration of the organicphase under reduced pressure gave the crude product, which was purifiedby silica gel column chromatography using 50-100% EtOAc/Pet. Spiritfollowed by 20% MeCN/EtOAc to give the product 550 (12.3 g, 88% over twosteps).

TLC rf 0.19 (70% EtOAc/Pet. Spirit)

HPLC t_(R) 7.06 min

MS (ESI) 553.3 (M+1)

Example 96 Synthesis of Compound 551 tert-butyl2-{(2S,7S)-7-aminomethyl-3-oxo-4-[(S)-2-phenylbutyl]-1,4-diazepan-2-yl}ethylcarbamate

A mixture of Cbz-protected product 550 (12.3 g, 22.3 mmol) and 5% Pd/C(2 g) in MeOH (100 mL) was shaken at room temperature under hydrogen atatmospheric pressure for one hour. The mixture was then filtered througha pad of Celite®, and the filtrate was concentrated under reducedpressure to give the crude amine 551. The crude material was used in thenext step without further purification.

HPLC t_(R) 5.77 min

MS (ESI) 419.3 (M+1)

Example 97 Synthesis of Compound 552 tert-butyl2-((2S,7S)-7-((6-chloro-2-naphthamido)methyl)-3-oxo-4-((S)-2-phenylbutyl)-1,4-diazepan-2-yl)ethylcarbamate

To a solution of the free amine 551 and 6-chloro-2-naphthoic acid (4.58g, 22.3 mmol) in DCM (125 ml) was added diisopropylethylamine (7.74 mL,44.5 mmol) and BOP (9.84 g, 22.3 mmol) at room temperature. Theresulting mixture was stirred for 16 hours then DCM was removed underreduced pressure. The residue was taken up in EtOAc (80 mL), then washedwith saturated NaHCO₃(aq) (100 mL×5), brine (100 mL) and dried overMgSO₄. Filtration and concentration of the organic phase gave the crudematerial, which was purified by silica gel column chromatography using80-100% EtOAc/Pet. Spirit as eluent to give the product 552 (10.7 g,79%).

TLC rf 0.31 (80% EtOAc/Pet. Spirit)

HPLC t_(R) 7.66 min

MS (ESI) 607.2 (M+1)

Example 98 Synthesis of Compound 441N-(((3S,5S)-3-(2-aminoethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-6-chloro-2-naphthamide

To the Boc protected material 552 (10.7 g, 17.6 mmol) in DCM (26 mL) wasadded TFA (26 ml) in one portion, the resulting mixture was stirred atroom temperature for one hour. DCM was removed under reduced pressureand the residue was taken up in EtOAc (30 mL), washed with saturatedNaHCO₃(aq) (30 mL×3), brine (30 mL) and dried over MgSO₄. Filtration andconcentration of the organic phase under reduced pressure gave the crudeamine 441, which was used in the next step without further purification.

HPLC t_(R) 5.98 min

MS (ESI) 507.0 (M+1)

Example 99 Synthesis of Compound 4066-chloro-N-(((3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)-2-naphthamide

To a mixture of crude amine 441 in CH₃CN (800 mL) was added1,5-dibromopentane (23.9 mL, 175.7 mmol) followed by K₂CO₃ (48.6 g,351.4 mmol). The resulting mixture was stirred at room temperature for44 hours, monitored by HPLC for conversion of sm (6.0 min) to product(6.4 min), avoiding extended reaction times leading to overalkylation togenerate a bromopentyl-alkylated byproduct (7.1 min). During isolation,excessive heating/concentration of the crude solution must be avoidedbefore removal of excess dibromopropane, to avoid overalkylation of thepiperidine ring. The K₂CO₃ was removed by filtration through a pad ofCelite®, and the filtrate was washed with Pet. Spirit (800 mL×2). TheMeCN phase was concentrated under reduced pressure to 400 mL, and waswashed with Pet. Spirit (400 mL×2). The MeCN was further concentratedunder reduced pressure to 200 mL, and was washed with Pet. Spirit (200mL×2). Evaporation of the final Pet. Spirit washing showed no more1,5-dibromopentane was extracted, so the MeCN phase was concentratedunder reduced pressure.

Aminopropyl-functionalized TLC rf 0.05-0.47 (80% EtOAc/Pet. Spirit)

Analytical HPLC t_(R) 6.41 min

MS (ESI) 575.2 (M+1).

The crude product was purified by a combination of flash columnchromatography over aminopropyl-functionalized silica gel, and/or byrecrystallization from acetonitrile.

Flash column: To a column packed with amino propyl-functionalized silicagel (154 g) in 20% ethyl acetate/petroleum spirit was loaded the crudefree base oil (7.2 g). The column was eluted with 20% ethylacetate/petroleum spirit (150 mL), followed by 50% ethylacetate/petroleum spirit (150 mL), 80% ethyl acetate/petroleum spirit(150 mL×2), 100% ethyl acetate (150 mL) and finally 100% acetonitrile(150 mL). Fractions containing 406 were combined and evaporated todryness to yield a white crystalline solid.

Crystallization: The white crystalline solid (2.87 g) obtained by columnpurification was dissolved in boiling acetonitrile (50 mL) 85° C.Activated carbon (Darco® G-60, −100 mesh, Sigma-Aldrich) (200 mg) wasadded to remove colour impurity. A further portion of acetonitrile (50mL) was added, and the resulting mixture was heated to boiling for 5min. The charcoal was filtered off while the solution was hot, with thefilter paper and the charcoal rinsed with hot acetonitrile (25 mL). Theclear acetonitrile solution was reduced down to 50 mL and left to standto cool to room temperature for 16 h. The white crystals were filteredoff and dried by suction to give 2.22 g (99.0% pure by HPLC analysis).An additional 117.2 mg (93.3% purity) was recovered by additionalcrystallization from the filtrate.

Conversion to bisHCl Salt: The free base (2.4229 g, 42.1 mmol) wassuspended in a 1:1 mixture of acetonitrile and milliQ H₂O (10 mL). Asolution of 1 M HCl (aq.) was added until all the solids dissolved(approximately 5 mL). An additional quantity of milliQ H₂O was thenadded (20 mL) and the resulting solution frozen and lypholisedovernight, resulting in a white powder (2.61 g, 95.6% yield).

HPLC t_(R) 6.27 min

MS (ESI) 575.1 (M+1).

¹H NMR (600 MHz, CDCl₃): δ 0.75 (t, 3 H, J=7.2 Hz), 1.40 (m, 1 H), 1.56(m, 1 H), 1.65 (m, 1 H), 1.76˜1.90 (m, 4 H), 1.90˜2.06 (m, 2 H), 2.13(m, 1 H), 2.30 (br, 1 H), 2.57 (m, 1 H), 2.64˜2.86 (m, 4 H), 2.90˜3.10(m, 2 H), 3.25 (dd, 1 H, J=15.2, 10.4 Hz), 3.53 (m, 2 H), 3.70˜3.85 (m,3 H), 4.00 (m, 2 H), 4.10 (dd, 1 H, J=13.6, 5.6 Hz), 4.45 (m, 1 H), 7.10(d, 2 H, J=7.2 Hz), 7.18 (t, 1 H, J=7.2 Hz), 7.26 (t, 1 H, J=7.2 Hz),7.37 (dd, 1 H, J=9.0, 1.8 Hz), 7.71 (d, 1 H, J=8.4 Hz), 7.75 (s, 1 H),7.86 (d, 1 H, J=9.0 Hz), 8.09 (d, 1 H, J=9.0 Hz), 8.64 (s, 1 H), 8.68(m, 1 H), 9.85 (br, 1 H).

¹³C NMR (100 MHz, CDCl₃): δ 11.78, 21.86, 23.08 (2), 24.59, 26.14,28.09, 42.01, 46.24, 47.22, 53.14, 53.53, 54.03, 56.74, 57.79, 61.96,125.35, 126.24, 126.89, 127.20, 127.33, 127.85, 128.51, 128.72, 130.69,130.76, 130.91, 133.48, 135.28, 142.29, 167.18, 167.74

Example 100 Synthesis of Compound 5406-chloro-N-(([5,6,6-²H₃](3S,5S)-2-oxo-1-((S)-2-phenylbutyl)-3-(2-(piperidin-1-yl)ethyl)-1,4-diazepan-5-yl)[²H₂]methyl)-2-naphthamide

Compound 540 was synthesized according to the procedures in Examples92-99, except that the Fmoc deprotection/reductive amination steps ofExamples 94 and 95 were replaced by the following procedures in order tointroduce the deuterium atoms.

To a solution of (S)-9-fluorenylmethyl10-[(S)-2-phenylbutyl]-2,2-dimethyl-18-phenyl-4,9,13,16-tetraoxo-3,17-dioxa-5,10,15-triazaoctadecan-8-ylcarbamate548 (370.5 mg, 0.47 mmol) in dry THF (7.5 ml) was added drytriethylamine (7.5 mL, 54 mmol) in one portion at room temperaturefollowed by D₂O (99.96 atom % deuterium, 3.0 ml, 168 mmol). This mixturewas stirred under nitrogen at room temperature for 16 h, with thereaction mixture used in the next step without isolation.

MS (ESI) 573.0 (M+1).

t_(R) 6.95 min.

To the crude deuterium exchange reaction mixture was added NaBD₃CN (152mg, 2.31 mmol) in one portion, with the reaction stirred at roomtemperature for 24 h. A further portion of NaBD₃CN (182.4 mg, 3.28 mmol)was added and stirring continued at room temperature for 24 h. Thereaction was quenched by the addition of saturated NaHCO₃(aq) and theaqueous mixture extracted with EtOAc (3×10 mL×3). The combined organicextracts were washed with brine (15 mL), dried over MgSO₄ andconcentrated in vacuo. Flash chromatography (60% EtOAc/Pet. Spirit)yielded the product (175.8 mg, 67%).

TLC R_(f) 0.32 (70% EtOAc/Pet. Spirit)

Analytical HPLC t_(R) 7.06 min; MS (ESI) m/z 558.0 (M+1), 559.0, 557.0,560.0.

Example 101 Syntheses of Compounds 106-540

Compounds 106-540, with substituents as identified in Table 1, wereprepared as in the previous examples according to the routes identifiedin Schemes 1-5, as summarized in Table 2, with experimental propertiessummarized in Table 4.

TABLE 1 Identity of Compounds Cpd. R¹X R² R³ Y ZN(R^(4a))(R^(4b)) W 142-naphthoyl H H CH₂ (CH₂)₃NHC(═NH)NH₂ 3,5-dichlorobenzyl 256-fluoro-2-naphthoyl H H CH₂ (CH₂)₂N(CH₂CH₃)₂ 2,2-diphenylethyl 316-fluoro-2-naphthoyl H H CH₂ (CH₂)₂NH₂ 2,2-diphenylethyl 334-chlorocinnamoyl H H CH₂ (CH₂)₂(1-piperidinyl)) 2,2-diphenylethyl 372-naphthoyl H H CH₂ (CH₂)₂NH₂ 2-phenylbutyl 38 2-naphthoyl H H CH₂(CH₂)₂(1-piperidinyl) (S)-2-phenylbutyl 39 2-naphthoyl H H CH₂(CH₂)₂(1-piperidinyl) (R)-2-phenylbutyl 49 2-naphthoyl H H CH₂ (CH₂)₂NH₂3,5-dichlorobenzyl 50 2-naphthylsulfonyl H H CH₂ (CH₂)₃NHC(═NH)NH₂2,2-diphenylethyl 54 2-naphthoyl H H CH₂ (CH₂)₂NH₂ 2-ethylbutyl 606-bromo-2-naphthoyl Me H CH₂ (CH₂)₃NH₂ 2,2-diphenylethyl 626-bromo-2-naphthoyl H Me CH₂ (CH₂)₃NH₂ 2,2-diphenylethyl 63 2-naphthoylH H CH₂ (CH₂)₃NH₂ 2,2-diphenylethyl 64 2-naphthoyl H H CH₂(CH₂)₃(1-piperidinyl) 2,2-diphenylethyl 65 2-naphthoyl H H CH₂(CH₂)₃NHCH(CH₃)₂ 2,2-diphenylethyl 67 2-naphthoyl H H CH₂(CH₂)₃NHC(═NH)NHMe 2,2-diphenylethyl 71 2-naphthoyl H H CH₂ (CH₂)₃NHMe2,2-diphenylethyl 79 acetyl H H (S)-CHCH₂- (CH₂)₃NHC(═NH)NH₂2,2-diphenylethyl (2-naphthyl) 81 Ac-L-His H H (S)-CHCH₂-(CH₂)₃NHC(═NH)NH₂ 2,2-diphenylethyl (2-naphthyl) 83 propyloxycarbonyl HH (S)-CHCH₂- (CH₂)₃NHC(═NH)NH₂ 2,2-diphenylethyl (2-naphthyl) 85 acetylH H (R)-CHCH₂- (CH₂)₃NHC(═NH)NH₂ 2,2-diphenylethyl (2-naphthyl) 86Ac-L-His H H (R)-CHCH₂- (CH₂)₃NHC(═NH)NH₂ 2,2-diphenylethyl (2-naphthyl)87 propyloxycarbonyl H H (R)-CHCH₂- (CH₂)₃NHC(═NH)NH₂ 2,2-diphenylethyl(2-naphthyl) 105 2-naphthoyl H H CH₂ (CH₂)₃NHC(═NH)NH₂ 2,2-diphenylethyl106 4-biphenylcarbonyl H H CH₂ (CH₂)₃NH₂ 2,2-diphenylethyl 107indole-2-carbonyl H H CH₂ (CH₂)₃NH₂ 2,2-diphenylethyl 1084-biphenylcarbonyl H H CH₂ (CH₂)₃NHC(═NH)NH₂ 2,2-diphenylethyl 109indole-2-carbonyl H H CH₂ (CH₂)₃NHC(═NH)NH₂ 2,2-diphenylethyl 1102-naphthylacetyl H H CH₂ (CH₂)₃NHC(═NH)NH₂ 2,2-diphenylethyl 1111,2,3,4-tetrahydro-2- H H CH₂ (CH₂)₃NHC(═NH)NH₂ 2,2-diphenylethylnaphthoyl 112 quinolin-3-carbonyl H H CH₂ (CH₂)₃NHC(═NH)NH₂2,2-diphenylethyl 113 quinoxaline-2- H H CH₂ (CH₂)₃NHC(═NH)NH₂2,2-diphenylethyl carbonyl 114 isoquinoline-3- H H CH₂ (CH₂)₃NHC(═NH)NH₂2,2-diphenylethyl carbonyl 115 benzoyl H H CH₂ (CH₂)₃NHC(═NH)NH₂2,2-diphenylethyl 116 quinaldoyl H H CH₂ (CH₂)₃NHC(═NH)NH₂2,2-diphenylethyl 117 2-naphthoyl H H CH₂ (CH₂)₄NH₂ 1-naphthylmethyl 1182-naphthylacetyl H H CH₂ (CH₂)₄NH₂ 1-naphthylmethyl 119 1-naphthoyl H HCH₂ (CH₂)₄NH₂ 1-naphthylmethyl 120 indole-3-acetyl H H CH₂ (CH₂)₄NH₂1-naphthylmethyl 121 4-biphenylacetyl H H CH₂ (CH₂)₄NH₂ 2-naphthylmethyl122 2-naphthoyl H H CH₂ (CH₂)₄NH₂ 2-naphthylmethyl 123 2-naphthylacetylH H CH₂ (CH₂)₄NH₂ 2-naphthylmethyl 124 1-naphthoyl H H CH₂ (CH₂)₄NH₂2-naphthylmethyl 125 1-naphthylacetyl H H CH₂ (CH₂)₄NH₂ 2-naphthylmethyl126 2-naphthoyl H H CH₂ (CH₂)₄NH₂ 2,2-diphenylethyl 127 S-Tic H H CH₂(CH₂)₄NH₂ 2,2-diphenylethyl 128 R-Tic H H CH₂ (CH₂)₄NH₂2,2-diphenylethyl 129 2-benzofurananoyl H H CH₂ (CH₂)₄NH₂2,2-diphenylethyl 130 R-Tic H H CH₂ (CH₂)₃NHC(═NH)NHMe 2,2-diphenylethyl131 S-Tic H H CH₂ (CH₂)₃NHC(═NH)NH₂ 2,2-diphenylethyl 1322-benzofuranoyl H H CH₂ (CH₂)₃NHC(═NH)NH₂ 2,2-diphenylethyl 133indane-2-carbonyl H H CH₂ (CH₂)₃NHC(═NH)NH₂ 2,2-diphenylethyl 134 R-TicH H CH₂ (CH₂)₃NHC(═NH)NH₂ 2,2-diphenylethyl 135 benzothiophene-2- H HCH₂ (CH₂)₃NHC(═NH)NH₂ 2,2-diphenylethyl carbonyl 136 2,4-dichlorobenzoylH H CH₂ (CH₂)₃NHC(═NH)NH₂ 2,2-diphenylethyl 137 2,5-dichlorobenzoyl H HCH₂ (CH₂)₃NHC(═NH)NH₂ 2,2-diphenylethyl 138 benzoyl H H CH₂(CH₂)₃NHC(═NH)NH₂ 2,2-diphenylethyl 139 cyclohexanoyl H H CH₂(CH₂)₃NHC(═NH)NH₂ 2,2-diphenylethyl 140 3-phenoxybenzoyl H H CH₂(CH₂)₃NHC(═NH)NH₂ 2,2-diphenylethyl 141 4-phenoxybenzoyl H H CH₂(CH₂)₃NHC(═NH)NH₂ 2,2-diphenylethyl 142 indole-2-carbonyl H H CH₂(CH₂)₃NHC(═NH)NH₂ 2,2-diphenylethyl 143 3-phenylpropanoyl H H CH₂(CH₂)₃NHC(═NH)NH₂ 2,2-diphenylethyl 144 3,4-dimethylbenzoyl H H CH₂(CH₂)₃NHC(═NH)NH₂ 2,2-diphenylethyl 145 4-tert-butylbenzoyl H H CH₂(CH₂)₃NHC(═NH)NH₂ 2,2-diphenylethyl 146 2,4-dimethoxybenzoyl H H CH₂(CH₂)₃NHC(═NH)NH₂ 2,2-diphenylethyl 147 cyclohexylacetyl H H CH₂(CH₂)₃NHC(═NH)NH₂ 2,2-diphenylethyl 148 piperonyloyl H H CH₂(CH₂)₃NHC(═NH)NH₂ 2,2-diphenylethyl 149 benzimidazole-5- H H CH₂(CH₂)₃NHC(═NH)NH₂ 2,2-diphenylethyl carbonyl 150 benzotriazole-5- H HCH₂ (CH₂)₃NHC(═NH)NH₂ 2,2-diphenylethyl carbonyl 151 cyclopentanoyl H HCH₂ (CH₂)₃NHC(═NH)NH₂ 2,2-diphenylethyl 152 3,4-dichlorobenzoyl H H CH₂(CH₂)₃NHC(═NH)NH₂ 2,2-diphenylethyl 153 trans-cinnamoyl H H CH₂(CH₂)₃NHC(═NH)NH₂ 2,2-diphenylethyl 154 3,5-dichlorobenzoyl H H CH₂(CH₂)₃NHC(═NH)NH₂ 2,2-diphenylethyl 155 2,4-dichloro- H H CH₂(CH₂)₃NHC(═NH)NH₂ 2,2-diphenylethyl phenylacetyl 156 1-methoxy-2- H HCH₂ (CH₂)₃NHC(═NH)NH₂ 2,2-diphenylethyl naphthoyl 157 3,4-dichloro- H HCH₂ (CH₂)₃NHC(═NH)NH₂ 2,2-diphenylethyl phenylacetyl 158 6-methoxy-2- HH CH₂ (CH₂)₃NHC(═NH)NH₂ 2,2-diphenylethyl naphthoyl 159 2,4-dichloro- HH CH₂ (CH₂)₃NHC(═NH)NH₂ 2,2-diphenylethyl cinnamoyl 160 adamantane-1- HH CH₂ (CH₂)₃NHC(═NH)NH₂ 2,2-diphenylethyl carbonyl 161 phenoxyacetyl H HCH₂ (CH₂)₃NHC(═NH)NH₂ 2,2-diphenylethyl 162 3-methoxy-2-napthoyl H H CH₂(CH₂)₃NHC(═NH)NH₂ 2,2-diphenylethyl 163 4-bromobenzoyl H H CH₂(CH₂)₃NHC(═NH)NH₂ 2,2-diphenylethyl 164 S-benzodioxan-2- H H CH₂(CH₂)₃NHC(═NH)NH₂ 2,2-diphenylethyl carbonyl 165 4-chlorocinnamoyl H HCH₂ (CH₂)₃NHC(═NH)NH₂ 2,2-diphenylethyl 166 3-(2-thienyl)acryloyl H HCH₂ (CH₂)₃NHC(═NH)NH₂ 2,2-diphenylethyl 167 R-benzodioxan-2- H H CH₂(CH₂)₃NHC(═NH)NH₂ 2,2-diphenylethyl carbonyl 168 4-hydroxycinnamoyl H HCH₂ (CH₂)₃NHC(═NH)NH₂ 2,2-diphenylethyl 169 2-methoxycinnamoyl H H CH₂(CH₂)₃NHC(═NH)NH₂ 2,2-diphenylethyl 170 4-methylcinnamoyl H H CH₂(CH₂)₃NHC(═NH)NH₂ 2,2-diphenylethyl 171 2-trifluoromethyl- H H CH₂(CH₂)₃NHC(═NH)NH₂ 2,2-diphenylethyl cinnamoyl 172 3-fluorocinnamoyl H HCH₂ (CH₂)₃NHC(═NH)NH₂ 2,2-diphenylethyl 173 alpha-methyl H H CH₂(CH₂)₃NHC(═NH)NH₂ 2,2-diphenylethyl cinnamoyl 174 trans-2- H H CH₂(CH₂)₃NHC(═NH)NH₂ 2,2-diphenylethyl phenylcyclopropane- 1-carbonyl 1752,4-dichloro- H H CH₂ (CH₂)₃NHC(═NH)NH₂ 2,2-diphenylethyl phenoxyacetyl176 3-chlorocinnamoyl H H CH₂ (CH₂)₃NHC(═NH)NH₂ 2,2-diphenylethyl 1771,3-benzothiazole-6- H H CH₂ (CH₂)₃NHC(═NH)NH₂ 2,2-diphenylethylcarbonyl 178 5-phenyl-2-furoyl H H CH₂ (CH₂)₃NHC(═NH)NH₂2,2-diphenylethyl 179 3-methoxycinnamoyl H H CH₂ (CH₂)₃NHC(═NH)NH₂2,2-diphenylethyl 180 6-bromo-2-naphthoyl H H CH₂ (CH₂)₃NHC(═NH)NH₂2,2-diphenylethyl 181 2-naphthoyl H H CH₂ (CH₂)₃NHC(═NH)NH₂ phenethyl182 2-naphthoyl H H CH₂ (CH₂)₃NHC(═NH)NH₂ 3,4-dichlorophenethyl 1832-naphthoyl H H CH₂ (CH₂)₃NHC(═NH)NH₂ 2,4-dichlorophenethyl 184benzothiophene-5- H H CH₂ (CH₂)₃NHC(═NH)NH₂ 2,2-diphenylethyl carbonyl185 3-methyl-2-phenyl- H H CH₂ (CH₂)₃NHC(═NH)NH₂ 2,2-diphenylethylpyrazole-4-carbonyl 186 4-methoxycinnamoyl H H CH₂ (CH₂)₃NHC(═NH)NH₂2,2-diphenylethyl 187 6-fluoro-2-naphthoyl H H CH₂ (CH₂)₃NHC(═NH)NH₂2,2-diphenylethyl 188 2-chlorocinnamoyl H H CH₂ (CH₂)₃NHC(═NH)NH₂2,2-diphenylethyl 189 2-hydroxycinnamoyl H H CH₂ (CH₂)₃NHC(═NH)NH₂2,2-diphenylethyl 190 3-methylcinnamoyl H H CH₂ (CH₂)₃NHC(═NH)NH₂2,2-diphenylethyl 191 3-trifluoromethyl- H H CH₂ (CH₂)₃NHC(═NH)NH₂2,2-diphenylethyl cinnamoyl 192 3-hydroxycinnamoyl H H CH₂(CH₂)₃NHC(═NH)NH₂ 2,2-diphenylethyl 193 2-fluorocinnamoyl H H CH₂(CH₂)₃NHC(═NH)NH₂ 2,2-diphenylethyl 194 2-methylcinnamoyl H H CH₂(CH₂)₃NHC(═NH)NH₂ 2,2-diphenylethyl 195 alpha-fluorocinnamoyl H H CH₂(CH₂)₃NHC(═NH)NH₂ 2,2-diphenylethyl 196 2-naphthoyl H H CH₂4-piperidinyl 2,2-diphenylethyl 197 2-naphthoyl H H CH₂CH₂(4-piperidinyl) 2,2-diphenylethyl 198 4-fluorocinnamoyl H H CH₂(CH₂)₃NHC(═NH)NH₂ 2,2-diphenylethyl 199 4-trifluoromethyl- H H CH₂(CH₂)₃NHC(═NH)NH₂ 2,2-diphenylethyl cinnamoyl 200 2-naphthoyl H H CH₂(CH₂)₃NHC(═NH)NH₂ 2,2-diphenylpropyl 201 2-naphthoyl H H CH₂(CH₂)₃NHC(═NH)NH₂ cyclohexanemethyl 202 2-naphthoyl H H CH₂(CH₂)₃NHC(═NH)NH₂ 1-adamantane-methyl 203 2-naphthoyl H H CH₂(CH₂)₃NHC(═NH)NH₂ (S)-1,1-diphenyl-2- propyl 204 2-naphthoyl H H CH₂(CH₂)₃NHC(═NH)NH₂ (R)-1,1-diphenyl-2- propyl 205 2-naphthoyl H H CH₂(CH₂)₃NHC(═NH)NH₂ cyclohexyl 206 2-naphthoyl H H CH₂ (CH₂)₃NHC(═NH)NH₂(R)-1,1-diphenyl-1- fluoro-2-propyl 207 2,6-difluorocinnamoyl H H CH₂(CH₂)₃NHC(═NH)NH₂ 2,2-diphenylethyl 208 2-chloro-6- H H CH₂(CH₂)₃NHC(═NH)NH₂ 2,2-diphenylethyl fluorocinnamoyl 209 4-bromocinnamoylH H CH₂ (CH₂)₃NHC(═NH)NH₂ 2,2-diphenylethyl 210 4-ethoxycinnamoyl H HCH₂ (CH₂)₃NHC(═NH)NH₂ 2,2-diphenylethyl 211 6-bromonaphthoyl H H CH₂(CH₂)₃NH₂ 2,2-diphenylethyl 212 trans-cinnamoyl H H CH₂ (CH₂)₃NH₂2,2-diphenylethyl 213 4-chlorocinnamoyl H H CH₂ (CH₂)₃NH₂2,2-diphenylethyl 214 1,4-dimethoxy-2- H H CH₂ (CH₂)₃NHC(═NH)NH₂2,2-diphenylethyl naphthoyl 215 2-naphthoyl H H CH₂ (CH₂)₃NHC(═NH)N(Me)₂2,2-diphenylethyl 216 6-hydroxy-2- H H CH₂ (CH₂)₃NHC(═NH)NH₂2,2-diphenylethyl naphthoyl 217 6-amino-2-naphthoyl H H CH₂(CH₂)₃NHC(═NH)NH₂ 2,2-diphenylethyl 218 4-Me cinnamoyl H H CH₂ (CH₂)₃NH₂2,2-diphenylethyl 219 4-fluoro cinnamoyl H H CH₂ (CH₂)₃NH₂2,2-diphenylethyl 220 6-fluoro-2-napthoyl H H CH₂ (CH₂)₃NH₂2,2-diphenylethyl 221 2-ethylhexanoyl H H CH₂ (CH₂)₃NH₂2,2-diphenylethyl 222 3,4-dimethylbenzoyl H H CH₂ (CH₂)₃NH₂2,2-diphenylethyl 223 3,4-dichlorobenzoyl H H CH₂ (CH₂)₃NH₂2,2-diphenylethyl 224 2-ethylhexanoyl H H CH₂ (CH₂)₃NHC(═NH)NH₂2,2-diphenylethyl 225 2-naphthoyl H H CH₂ (CH₂)₃NH(cyclohexyl)2,2-diphenylethyl 226 2-naphthoyl H H CH₂ (CH₂)₃NHC(═NH)NH₂ 2-naphthyl227 2-naphthoyl H H CH₂ (CH₂)₃NHC(═NH)NH₂ (9-fluorenyl)methyl 2284-fluorocinnamoyl H H CH₂ (CH₂)₃NH(cyclohexyl) 2,2-diphenylethyl 2292-naphthoyl H H CH₂ (CH₂)₄NHCH(CH₃)₂ 2,2-diphenylethyl 2302,4-difluorocinnamoyl H H CH₂ (CH₂)₃NH₂ 2,2-diphenylethyl 2314-cyanocinnamoyl H H CH₂ (CH₂)₃NH₂ 2,2-diphenylethyl 2323-(2-naphthyl)acryloyl H H CH₂ (CH₂)₃NH₂ 2,2-diphenylethyl 233 4-fluoro-H H CH₂ (CH₂)₃NH₂ 2,2-diphenylethyl phenoxyacetyl 2345-(4-chlorophenyl)-2- H H CH₂ (CH₂)₃NH₂ 2,2-diphenylethyl furoyl 2354-(pyrrol-1-yl)-benzoyl H H CH₂ (CH₂)₃NH₂ 2,2-diphenylethyl 2362-oxo-1-phenyl- H H CH₂ (CH₂)₃NH₂ 2,2-diphenylethylpyrrolidine-3-carbonyl 237 5-(4-chlorophenyl)- H H CH₂ (CH₂)₃NH₂2,2-diphenylethyl isoxazole-3-carbonyl 238 5-(2-furyl)-isoxazole- H HCH₂ (CH₂)₃NH₂ 2,2-diphenylethyl 3-carbonyl 239 2-phenyl-4-thiazole H HCH₂ (CH₂)₃NH₂ 2,2-diphenylethyl carbonyl 240 4-(3,5-dimethyl1H-- H H CH₂(CH₂)₃NH₂ 2,2-diphenylethyl pyrazol-1-yl) benzoyl 241 3-methyl-2-phenylH H CH₂ (CH₂)₃NH₂ 2,2-diphenylethyl pyrazole-4-carbonyl 242 2-naphthoylH H CH₂ (CH₂)₃NHC(═NH)NH₂ cyclohexaneethyl 243 2-naphthoyl H H CH₂(CH₂)₃NHC(═NH)NH₂ 2-norbornaneethyl 244 2-naphthoyl H H CH₂(CH₂)₃NHC(═NH)NH₂ 2,2-bis(4- methoxyphenyl)ethyl 245 2-naphthoyl H H CH₂(CH₂)₄NHCH₂Ph 2,2-diphenylethyl 246 2-naphthoyl H H CH₂(CH₂)₄NH(cyclopentyl) 2,2-diphenylethyl 247 2-naphthoyl H H CH₂(CH₂)₄NH(cyclobutyl) 2,2-diphenylethyl 248 2-naphthoyl H H CH₂(CH₂)₄N(cyclobutyl)₂ 2,2-diphenylethyl 249 2-naphthoyl H H CH₂(CH₂)₃NHC(═NH)NH₂ benzyl 250 2-naphthoyl H H CH₂ (CH₂)₃NHC(═NH)NH₂2,2-bis(4- fluorophenyl)ethyl 251 2-naphthoyl H H CH₂ (CH₂)₃NHC(═NH)NH₂2-naphthalenemethyl 252 3-(5-methyl-2- H H CH₂ (CH₂)₃NH₂2,2-diphenylethyl thienyl)-acryloyl 253 5-phenyl-pyrazole-3- H H CH₂(CH₂)₃NH₂ 2,2-diphenylethyl carbonyl 254 4-fluorocinnamoyl Me H CH₂(CH₂)₃NH₂ 2,2-diphenylethyl 255 4-fluorocinnamoyl H Me CH₂ (CH₂)₃NH₂2,2-diphenylethyl 256 4-(3-methyl-5-oxo-2- H H CH₂ (CH₂)₃NH₂2,2-diphenylethyl pyrazolin-1yl)benzoyl 257 4-bromocinnamoyl H H CH₂(CH₂)₃NH₂ 2,2-diphenylethyl 258 4-chlorocinnamoyl H H CH₂(CH₂)₃(1-pyrrolidinyl) 2,2-diphenylethyl 259 4-chlorocinnamoyl H H CH₂(CH₂)₃(1-piperidinyl) 2,2-diphenylethyl 260 2-naphthoyl H H CH₂CH₂CH₂NH₂ 2,2-diphenylethyl 261 2-naphthoyl H H CH₂(CH₂)₃(1-pyrrolidinyl) 2,2-diphenylethyl 262 2-naphthoyl H H CH₂(CH₂)₃(1-azetidinyl) 2,2-diphenylethyl 263 2-naphthoyl H H CH₂(CH₂)₃NHC(═NH)NH₂ 1-naphthalenemethyl 264 2-naphthoyl H H CH₂(CH₂)₃NHC(═NH)NH₂ 2-(2-naphthyl)ethyl 265 2-naphthoyl H H CH₂(CH₂)₃NHC(═NH)NH₂ (S)-CH₂CH(Ph)NHCOMe 266 trans-cinnamoyl H H CH₂(CH₂)₃(1-piperidinyl) 2,2-diphenylethyl 267 3,4-dimethylbenzoyl H H CH₂(CH₂)₃(1-piperidinyl) 2,2-diphenylethyl 268 3,4-dichlorobenzoyl H H CH₂(CH₂)₃(1-piperidinyl) 2,2-diphenylethyl 269 2-naphthoyl H H CH₂(CH₂)₃NHC(═NH)NH₂ (S)-CH₂CH(Ph)—NHCOcBu 270 2-naphthoyl H H CH₂(CH₂)₃NHC(═NH)NH₂ (S)-CH₂CH(Ph)—NHCOcHex 271 2-naphthoyl H H CH₂ CH₂NH₂2,2-diphenylethyl 272 4-chlorocinnamoyl H H CH₂ CH₂NH₂ 2,2-diphenylethyl273 4-fluorocinnamoyl H H CH₂ (CH₂)₂NH₂ 2,2-diphenylethyl 2744-methylcinnamoyl H H CH₂ (CH₂)₂NH₂ 2,2-diphenylethyl 275 2-naphthoyl HH CH₂ CH₂(1-piperidinyl) 2,2-diphenylethyl 276 4-chlorocinnamoyl H H CH₂CH₂(1-piperidinyl) 2,2-diphenylethyl 277 3,4-dichlorobenzoyl H H CH₂(CH₂)₂NH₂ 2,2-diphenylethyl 278 3,4-dimethylbenzoyl H H CH₂ (CH₂)₂NH₂2,2-diphenylethyl 279 trans-cinnamoyl H H CH₂ (CH₂)₂NH₂2,2-diphenylethyl 280 4-chlorocinnamoyl H H CH₂ (CH₂)₂NH₂2,2-diphenylethyl 281 3,4-dichlorobenzoyl H H CH₂ (CH₂)₂(1-piperidinyl)2,2-diphenylethyl 282 3,4-dimethylbenzoyl H H CH₂ (CH₂)₂(1-piperidinyl)2,2-diphenylethyl 283 trans-cinnamoyl H H CH₂ (CH₂)₂(1-piperidinyl)2,2-diphenylethyl 284 4-fluorocinnamoyl H H CH₂ (CH₂)₂(1-piperidinyl)2,2-diphenylethyl 285 4-methylcinnamoyl H H CH₂ (CH₂)₂(1-piperidinyl)2,2-diphenylethyl 286 2-naphthoyl H H CH₂ (CH₂)₃NHC(═NH)NH₂3,5-dimethylbenzyl 287 2-naphthoyl H H CH₂ (CH₂)₃NHC(═NH)NH₂(S)-CH₂CH(Ph)NHCOPh 288 2-naphthoyl H H CH₂ (CH₂)₃NHC(═NH)NH₂(R)-CH₂CH(Ph)NHCOPh 289 2-naphthoyl H H CH₂ (CH₂)₃NHC(═NH)NH₂CH₂CH(Ph)OMe 290 2-naphthoyl H H CH₂ (CH₂)₃NHC(═NH)NH₂ CH₂CH(Ph)OnPr 2912-naphthoyl H H CH₂ (CH₂)₃NHC(═NH)NH₂ CH₂CH(Ph)OBn 292 2-naphthoyl H HCH₂ (CH₂)₃NHC(═NH)NH₂ CH₂CH(Ph)Oallyl 293 4-methylcinnamoyl H H CH₂(CH₂)₃NHCOCH3 2,2-diphenylethyl 294 4-methylcinnamoyl H H CH₂(CH₂)₃NHCO(cyclohexyl) 2,2-diphenylethyl 295 2-naphthoyl H H CH₂(CH₂)₃NHC(═NH)NH₂ CH₂CH(Ph)OPh 296 2-naphthoyl H H CH₂ (CH₂)₃NHC(═NH)NH₂CH₂CH(Ph)CO₂Et 297 2-naphthoyl H H CH₂ (CH₂)₃NHC(═NH)NH₂ 2-ethylbutyl298 2-naphthoyl H H CH₂ (CH₂)₃NHC(═NH)NH₂ 3,5-dimethylcyclohexyl- methyl299 4-chlorocinnamoyl H H CH₂ (CH₂)₂NHCO(cyclohexyl) 2,2-diphenylethyl300 4-chlorocinnamoyl H H CH₂ (CH₂)₂NHCOCH₂(cyclohexyl)2,2-diphenylethyl 301 benzoyl H H (CH₂)₂ (CH₂)₂NH₂ 2,2-diphenylethyl 3023,4-dichlorobenzoyl H H (CH₂)₂ (CH₂)₂NH₂ 2,2-diphenylethyl 3032-naphthoyl H H (CH₂)₂ (CH₂)₂NH₂ 2,2-diphenylethyl 304 benzoyl H H(CH₂)₂ (CH₂)₂(1-piperidinyl) 2,2-diphenylethyl 305 3,4-dichlorobenzoyl HH (CH₂)₂ (CH₂)₂(1-piperidinyl) 2,2-diphenylethyl 306 2-naphthoyl H H(CH₂)₂ (CH₂)₂(1-piperidinyl) 2,2-diphenylethyl 307 2-naphthoyl H H CH₂(CH₂)₃NHC(═NH)NH₂ CH₂CH(Ph)CONMe₂ 308 3,4-dichlorobenzoyl H H CH₂(CH₂)₂NH₂ 3,5-dichlorobenzyl 309 4-chlorocinnamoyl H H CH₂ (CH₂)₂NH₂3,5-dichlorobenzyl 310 2-naphthoyl H H CH₂ (CH₂)₃NHC(═NH)NH₂3-chloro-5-fluorobenzyl 311 2-naphthoyl H H CH₂ (CH₂)₃NHC(═NH)NH₂3,5-difluorobenzyl 312 2-naphthoyl H H CH₂ (CH₂)₃NH₂3-chloro-5-fluorobenzyl 313 2-naphthoyl H H CH₂ (CH₂)₃NH₂3,5-difluorobenzyl 314 2-naphthoyl H H CH₂ (CH₂)₃NH₂ 2,5-dichlorobenzyl315 2-naphthoyl H H CH₂ (CH₂)₃NH₂ 2,6-dichlorobenzyl 316 2-naphthoyl H HCH₂ (CH₂)₃NH₂ 3,5-dimethoxybenzyl 317 2-naphthoyl H H CH₂ (CH₂)₃NH₂2-chlorobenzyl 318 2-naphthoyl H H CH₂ (CH₂)₃NH₂ 2,3-dichlorobenzyl 3192-naphthoyl H H CH₂ (CH₂)₃NH₂ 2,4-dichlorobenzyl 320 2-naphthoyl H H CH₂(CH₂)₃NH₂ 3,4-dichlorobenzyl 321 2-naphthoyl H H CH₂ (CH₂)₃NH₂3-fluoro-5-methylbenzyl 322 2-naphthoyl H H CH₂ (CH₂)₃NH₂ 3-fluoro-5-(trifluoromethyl)benzyl 323 2-naphthoyl H H CH₂ (CH₂)₃NH₂ 4-chlorobenzyl324 2-naphthoyl H H CH₂ (CH₂)₃NH₂ 2-phenylbutyl 325 2-naphthoyl H H CH₂(CH₂)₃NH₂ 1-(1-phenylcyclohexyl)- methyl 326 3,4-dichlorobenzoyl H H CH₂(CH₂)₂(1-piperidinyl) 3,5-dichlorobenzyl 327 2-naphthoyl H H CH₂(CH₂)₂(1-piperidinyl) 3,5-dichlorobenzyl 328 4-chlorocinnamoyl H H CH₂(CH₂)₂(1-piperidinyl) 3,5-dichlorobenzyl 329 3,4-dichlorobenzoyl H H CH₂(CH₂)₂NH₂ 2-ethylbutyl 330 4-chlorocinnamoyl H H CH₂ (CH₂)₂NH₂2-ethylbutyl 331 4-chlorocinnamoyl H H CH₂ (CH₂)₂(1-piperidinyl)2-ethylbutyl 332 3,4-dichlorobenzoyl H H CH₂ (CH₂)₂(1-piperidinyl)2-ethylbutyl 333 2-naphthoyl H H CH₂ (CH₂)₂(1-piperidinyl) 2-ethylbutyl334 4-chloro-3-fluoro- H H CH₂ (CH₂)₂NH₂ 2-ethylbutyl benzoyl 3354-chloro-3-methyl- H H CH₂ (CH₂)₂NH₂₂ 2-ethylbutyl benzoyl 3363-chloro-4-fluoro- H H CH₂ (CH₂)₂NH₂ 2-ethylbutyl benzoyl 3373-chloro-4-methyl- H H CH₂ (CH₂)₂NH₂ 2-ethylbutyl benzoyl 3384-chlorocinnamoyl H H CH₂ CH₂(1-piperidinyl) 2-ethylbutyl 3392-naphthoyl H H (CH₂)₂ (CH₂)₂(1-pyrrolidinyl) 2,2-diphenylethyl 3402-naphthoyl H H CH₂ (CH₂)₃NH₂ 3,5-bis(trifluoromethyl)- benzyl 3412-naphthoyl H H CH₂ (CH₂)₃NH₂ 3-chlorobenzyl 342 2-naphthoyl H H CH₂(CH₂)₃(1-piperidinyl) 2-phenylbutyl 343 2-naphthoyl H H CH₂(CH₂)₃NHC(═NH)NH₂ CH₂CH(Ph)CON[—(CH₂)₅—] 344 2-naphthoyl H H CH₂(CH₂)₃NHC(═NH)NH₂ CH₂CH(Ph)CONHPh 345 3,4-dichlorobenzoyl H H (CH₂)₂(CH₂)₂NHCH(CH₃)₂ 2,2-diphenylethyl 346 3,4-dichlorobenzoyl H H (CH₂)₂(CH₂)₂N(CH(CH₃)₂)₂ 2,2-diphenylethyl 347 3,4-dichlorobenzoyl H H CH₂CH₂NH₂ 3,5-dichlorobenzyl 348 2-naphthoyl H H CH₂ CH₂NH₂3,5-dichlorobenzyl 349 4-chlorocinnamoyl H H CH₂ CH₂NH₂3,5-dichlorobenzyl 350 3,4-dichlorobenzoyl H H CH₂ CH₂(1-piperidinyl)3,5-dichlorobenzyl 351 4-chlorocinnamoyl H H CH₂ CH₂(1-piperidinyl)3,5-dichlorobenzyl 352 3,4-dichlorobenzoyl H H CH₂ (CH₂)₂NH₂2-phenylbutyl 353 4-chlorocinnamoyl H H CH₂ (CH₂)₂NH₂ 2-phenylbutyl 3543,4-dichlorobenzoyl H H CH₂ CH₂(1-pyrrolidinyl) 3,5-dichlorobenzyl 3552-naphthoyl H H CH₂ CH₂(1-pyrrolidinyl) 3,5-dichlorobenzyl 3562-naphthoyl H H CH₂ (CH₂)₃NH₂ (S)-β-methylphenethyl 357 2-naphthoyl H HCH₂ (CH₂)₃NH₂ (R)-β-methylphenethyl 358 2-naphthoyl H H CH₂(CH₂)₂N(CH₃)₂ 2,2-diphenylethyl 359 6-fluoro-2--napthoyl H H CH₂(CH₂)₃(1-piperidinyl) 2,2-diphenylethyl 360 2-naphthoyl H H CH₂(CH₂)₃NH₂ 3,5-diethynylbenzyl 361 4-chlorocinnamoyl H H CH₂(CH₂)₂N(CH₂CH₃)₂ 2,2-diphenylethyl 362 2-naphthoyl H H CH₂(CH₂)₂N(CH₂CH₃)₂ 2,2-diphenylethyl 363 3,4-dichlorobenzoyl H H CH₂(CH₂)₂(1-piperidinyl) (R)-2-phenylbutyl 364 4-chlorocinnamoyl H H CH₂(CH₂)₂(1-piperidinyl) (R)-2-phenylbutyl 365 4-chlorocinnamoyl H H CH₂(CH₂)₂(1-piperidinyl) (S)-2-phenylbutyl 366 6-chloro-2-naphthoyl H H CH₂(CH₂)₂NH₂ 2,2-diphenylethyl 367 2-naphthoyl H H CH₂(CH₂)₂(1-piperidinyl) 2,2-diphenylethyl 368 2-naphthoyl H H CH₂(CH₂)₂(1-piperidinyl) 2,2-diphenylethyl 369 6-fluoro-2-naphthoyl H H CH₂(CH₂)₂NH₂ 2-ethylbutyl 370 6-chloro-2-naphthoyl H H CH₂ (CH₂)₂NH₂2-ethylbutyl 371 6-bromo-2-naphthoyl H H CH₂ (CH₂)₂NH₂ 2-ethylbutyl 3726-fluoro-2-naphthoyl H H CH₂ (CH₂)₂(1-piperidinyl) 2-ethylbutyl 3736-chloro-2-naphthoyl H H CH₂ (CH₂)₂(1-piperidinyl) 2-ethylbutyl 3746-bromo-2-naphthoyl H H CH₂ (CH₂)₂(1-piperidinyl) 2-ethylbutyl 3753,4-dichlorobenzoyl H H CH₂ (CH₂)₂NH₂ 3,5-dimethylcyclohexyl 3762-naphthoyl H H CH₂ (CH₂)₂NH₂ 3,5-dimethylcyclohexyl 3774-chlorocinnamoyl H H CH₂ (CH₂)₂NH₂ 3,5-dimethylcyclohexyl 3786-chloro-2-naphthoyl H H CH₂ (CH₂)₂(1-piperidinyl) 2,2-diphenylethyl 3796-fluoro-2-naphthoyl H H CH₂ (CH₂)₂(1-piperidinyl) 2,2-diphenylethyl 3804-chlorocinnamoyl H H CH₂ (CH₂)₂(1-pyrrolidinyl) 2,2-diphenylethyl 3814-chlorocinnamoyl H H CH₂ (CH₂)₂NHCH(CH₃)₂ 2,2-diphenylethyl 3822-naphthoyl H H CH₂ (CH₂)₂NHCH(CH₃)₂ 2,2-diphenylethyl 3833,4-dichlorobenzoyl H H CH₂ (CH₂)₂NHCH(CH₃)₂ 2,2-diphenylethyl 3842-naphthoyl H H CH₂ (CH₂)₃NH₂ 2,6-dimethylcyclohexyl- methyl 3852-naphthoyl H H CH₂ (CH₂)₃NH₂ (S)-2-phenylbutyl 386 3,4-dichlorobenzoylH H CH₂ (CH₂)₂(1-piperidinyl) 3,5-dimethylcyclohexyl- methyl 3873,4-dichlorobenzoyl H H CH₂ (CH₂)₂NHCH(CH₃)₂ 3,5-dimethylcyclohexyl-methyl 388 2-naphthoyl H H CH₂ (CH₂)₂NH₂ 3-methyl-2-phenylbutyl 3892-naphthoyl H H CH₂ (CH₂)₂NH₂ (S)-2-phenylbutyl 390 2-naphthoyl H H CH₂(CH₂)₃NH₂ (R)-2-phenylbutyl 391 3-(4-chlorophenyl)- H H CH₂(CH₂)₂(1-piperidinyl) 2,2-diphenylethyl propanoyl 3923-(4-chlorophenyl)- H H CH₂ (CH₂)₂NH₂ 2,2-diphenylethyl propanoyl 3934-chlorocinnamoyl H H CH₂ CH₂NHCO(2-pyridyl) 2,2-diphenylethyl 3942-naphthoyl H H CH₂ (CH₂)₂(1-piperidinyl) (R)-3-methyl-2- phenylbutyl395 2-naphthoyl H H CH₂ (CH₂)₂(1-piperidinyl) (S)-3-methyl-2-phenylbutyl 396 4-isopropylcinnamoyl H H CH₂ (CH₂)₂(1-piperidinyl)2,2-diphenylethyl 397 4-isopropylcinnamoyl H H CH₂ (CH₂)₂NH₂2,2-diphenylethyl 398 2,4- H H CH₂ (CH₂)₂(1-piperidinyl)2,2-diphenylethyl dimethylcinnamoyl 399 2,4- H H CH₂ (CH₂)₂NH₂2,2-diphenylethyl dimethylcinnamoyl 400 2,4-difluorocinnamoyl H H CH₂(CH₂)₂(1-piperidinyl) 2,2-diphenylethyl 401 2,4-difluorocinnamoyl H HCH₂ (CH₂)₂NH₂ 2,2-diphenylethyl 402 4-chlorocinnamoyl H H CH₂CH₂NHCO(cyclohexyl) 2,2-diphenylethyl 403 4-chlorocinnamoyl H H CH₂(CH₂)₂(4-morpholinyl) 2,2-diphenylethyl 404 4-chlorocinnamoyl H H CH₂(CH₂)N[—C(Me)═CHCH═C(Me)—] 2,2-diphenylethyl 405 4-chlorocinnamoyl H HCH₂ CH₂CH₂(2,5-dimethyl-2- 2,2-diphenylethyl pyrrolidin-1-yl) 4066-chloro-2-naphthoyl H H CH₂ (CH₂)₂(1-piperidinyl) (S)-2-phenylbutyl 4074-chlorocinnamoyl H H CH₂ (CH₂)₂(1-pyrrolidinyl) (S)-2-phenylbutyl 4084-chlorocinnamoyl H H CH₂ (CH₂)₂NHCH(CH₃)₂ (S)-2-phenylbutyl 4096-chloro-2-naphthoyl H H CH₂ (CH₂)₂(1-pyrrolidinyl) (S)-2-phenylbutyl410 3,4-dichlorobenzoyl H H CH₂ (CH₂)₂(1-piperidinyl) (S)-2-phenylbutyl411 3,4-dichlorobenzoyl H H CH₂ (CH₂)₂(1-piperidinyl) (S)-2-phenylbutyl412 Cbz H H CH₂ (CH₂)₂(1-piperidinyl) 2,2-diphenylethyl 4134-bromocinnamoyl H H CH₂ (CH₂)₂(1-piperidinyl) 2,2-diphenylethyl 4145-(4-chlorophenyl)- H H CH₂ (CH₂)₂(1-piperidinyl) 2,2-diphenylethylisoxazole-3-carbonyl 415 6-chloro-2-naphthoyl H H CH₂ CH₂(1-piperidinyl)(S)-2-phenylbutyl 416 3,4-dichlorobenzoyl H H CH₂ CH₂(1-piperidinyl)(S)-2-phenylbutyl 417 6-chloro-2-naphthoyl H H CH₂ (CH₂)₃(1-piperidinyl)(S)-2-phenylbutyl 418 3,4-dichlorobenzoyl H H CH₂ (CH₂)₃(1-piperidinyl)(S)-2-phenylbutyl 419 4-chlorocinnamoyl H H C(Me)₂ (CH₂)₂NH₂2,2-diphenylethyl 420 4-chlorocinnamoyl H H C(Me)₂ (CH₂)₂(1-piperidinyl)2,2-diphenylethyl 421 2-naphthoyl H H CH₂ (CH₂)₂NH₂ (R)-2-(4-chloro-phenyl)propyl 422 2-naphthoyl H H CH₂ (CH₂)₂NH₂ 2-(4-chloro-phenyl)propyl 423 2-naphthoyl H H CH₂ (CH₂)₂(1-piperidinyl)(R)-2-(4-chloro- phenyl)propyl 424 2-naphthoyl H H CH₂(CH₂)₂(1-piperidinyl) (S)-2-(4-chloro- phenyl)propyl 4253,4-dichlorobenzoyl H H CH₂ (CH₂)₂N(phenyl)(CH₃) (S)-2-phenylbutyl 4263,4-dichlorobenzoyl H H CH₂ (CH₂)₂N(CH₂CH₃)₂ (S)-2-phenylbutyl 4273,4-dichlorobenzoyl H H CH₂ (CH₂)₂(4-morpholinyl) (S)-2-phenylbutyl 4283,4-dichlorobenzoyl H H CH₂ (CH₂)₂NH(phenyl) (S)-2-phenylbutyl 4293,4-dichlorobenzoyl H H CH₂ (CH₂)₂NH(benzyl) (S)-2-phenylbutyl 4303,4-dichlorobenzoyl H H CH₂ (CH₂)₂NHC(CH₃)₃ (S)-2-phenylbutyl 4313,4-dichlorobenzoyl H H CH₂ (CH₂)₂(4-CH₃-piperazin- (S)-2-phenylbutyl1-yl) 432 2-naphthoyl H H CH₂ (CH₂)₂(1-piperidinyl) (R)-2-phenylpentyl433 2-naphthoyl H H CH₂ (CH₂)₂(1-piperidinyl) (S)-2-phenylpentyl 434p-trifluoromethyl- H H CH₂ (CH₂)₂(1-piperidinyl) 2,2-diphenylethylbenzoyl 435 p-trifluoromethyl- H H CH₂ (CH₂)₂NH₂ 2,2-diphenylethylbenzoyl 436 m-trifluoromethyl- H H CH₂ (CH₂)₂(1-piperidinyl)2,2-diphenylethyl benzoyl 437 m-trifluoromethyl- H H CH₂ (CH₂)₂NH₂2,2-diphenylethyl benzoyl 438 6-chloro-2-naphthoyl H H CH₂(CH₂)₂NHCH(CH₃)₂ 3,5-dichlorobenzyl 439 3,4-dichlorobenzoyl H H CH₂(CH₂)₂NHCH(CH₃)₂ 3,5-dichlorobenzyl 440 6-chloro-2-naphthoyl H H CH₂(CH₂)₂NHCH(CH₃)₂ (S)-2-phenylbutyl 441 6-chloro-2-naphthoyl H H CH₂(CH₂)₂NH₂ (S)-2-phenylbutyl 442 3,4-dichlorobenzoyl H H CH₂(CH₂)₂N(benzyl)(CH₃) (S)-2-phenylbutyl 443 3,4-dichlorobenzoyl H H CH₂(CH₂)₂(piperazin-1-yl) (S)-2-phenylbutyl 444 3,4-dichlorobenzoyl H H CH₂(CH₂)₂N(n-pentyl)(CH₃) (S)-2-phenylbutyl 445 3,4-dichlorobenzoyl H H CH₂(CH₂)₂N[(CH(CH₃)₂]₂ (S)-2-phenylbutyl 446 3,4-dichlorobenzoyl H H CH₂(CH₂)₂(4-CH₃-piperidin- (S)-2-phenylbutyl 1-yl) 447 6-chloro-2-naphthoylH H CH₂ 4-piperidinyl (S)-2-phenylbutyl 448 6-chloro-2-naphthoyl H H CH₂1-isopentyl-4-piperidinyl (S)-2-phenylbutyl 449 3,4-dichlorobenzoyl H HCH₂ (CH₂)₂(3,5-Me₂- (S)-2-phenylbutyl piperidin-1-yl) 4503,4-dichlorobenzoyl H H CH₂ (CH₂)₂(4-OH-piperidin- (S)-2-phenylbutyl1-yl) 451 3,4-dichlorobenzoyl H H CH₂ (CH₂)₂(4-CO₂H- (S)-2-phenylbutylpiperidin-1-yl) 452 3,4-dichlorobenzoyl H H CH₂ (CH₂)₂NH[—(CH₂)₆—](S)-2-phenylbutyl 453 3,4-dichlorobenzoyl H H CH₂ (CH₂)₂[(S)-2-Me-(S)-2-phenylbutyl piperidin-1-yl] 454 3,4-dichlorobenzoyl H H CH₂(CH₂)₂N(tBu)(CH₃) (S)-2-phenylbutyl 455 6-chloro-2-naphthoyl H H CH₂1-ethyl-piperidin-4-yl (S)-2-phenylbutyl 456 3,4-dichlorobenzyl H H CH₂(CH₂)₂(1-piperidinyl) 2,2-diphenylethyl 457 6-chloro-2-naphthoyl H H CH₂(CH₂)₂NHC(═NH)NH₂ (S)-2-phenylbutyl 458 6-chloro-2-naphthoyl H H CH₂(CH₂)₂NHC(═NH)NHMe (S)-2-phenylbutyl 459 3,4-dichlorobenzoyl H H CH₂(CH₂)₂NH₂ (R)-2-isopropylbutyl 460 3,4-dichlorobenzoyl H H CH₂ (CH₂)₂NH₂(S)-2-isopropylbutyl 461 3,4-dichlorobenzoyl H H CH₂(CH₂)₂(1-piperidinyl) (R)-2-isopropylbutyl 462 3,4-dichlorobenzoyl H HCH₂ (CH₂)₂(1-piperidinyl) (S)-2-isopropylbutyl 463 6-chloro-2-naphthoylH H CH₂ CH₂C(Me₂)NH₂ (S)-2-phenylbutyl 464 3,4-dichlorobenzoyl H H CH₂(CH₂)₂NH₂ (S)-2-phenylbutyl 465 3,4-dichlorobenzoyl H H CH₂(CH₂)₂NHCH(CH₃)₂ (S)-2-phenylbutyl 466 6-chloro-2-naphthoyl H H CH₂(CH₂)₂NH₂ 3,5-dichlorobenzyl 467 6-chloro-2-naphthoyl H H CH₂(CH₂)₂(1-piperidinyl) 3,5-dichlorobenzyl 468 6-chloro-2-naphthoyl H HCH₂ CH₂C(Me₂)(1- (S)-2-phenylbutyl piperidinyl) 469 6-chloro-2-naphthoylH H CH₂ (CH₂)₂NH₂ (R)-2-isopropylbutyl 470 6-chloro-2-naphthoyl H H CH₂(CH₂)₂NH₂ (S)-2-isopropylbutyl 471 6-chloro-2-naphthoyl H H CH₂(CH₂)₂(1-piperidinyl) (R)-2-isopropylbutyl 472 6-chloro-2-naphthoyl H HCH₂ (CH₂)₂(1-piperidinyl) (S)-2-isopropylbutyl 473 6-carboxy-2- H H CH₂(CH₂)₂(1-piperidinyl) 2,2-diphenylethyl naphthoyl 4746-chloro-2-naphthoyl H H CH₂ (CH₂)₂NHC(═NH)NH—CH(CH₃)₂ (S)-2-phenylbutyl475 3,4-dichlorobenzoyl H H CH₂ (CH₂)₂NH₂ 2-ethyl-3-methyl-but-3- enyl476 3,4-dichlorobenzoyl H H CH₂ (CH₂)₂(1-piperidinyl)2-ethyl-3-methyl-but-3- enyl 477 6-chloro-2-naphthoyl H H CH₂ (CH₂)₂NH₂2-ethyl-3-methyl-but-3- enyl 478 6-chloro-2-naphthoyl H H CH₂(CH₂)₂(1-piperidinyl) (R)-2-ethyl-3-methyl- but-3-enyl 4796-chloro-2-naphthoyl H H CH₂ (CH₂)₂(1-piperidinyl) (S)-2-ethyl-3-methyl-but-3-enyl 480 4-biphenylcarboxylyl H H CH₂ (CH₂)₃NHC(═NH)NH₂cyclohexanemethyl 481 indole-3-acetyl H H CH₂ (CH₂)₃NHC(═NH)NH₂cyclohexanemethyl 482 3-quinolinecarboxylyl H H CH₂ (CH₂)₃NHC(═NH)NH₂cyclohexanemethyl 483 3,4-dichlorobenzoyl H H CH₂ (CH₂)₂(4,4-difluoro-1-(S)-2-phenylbutyl piperidinyl) 484 3,4-dichlorobenzoyl H H CH₂(CH₂)₂(3,3-difluoro-1- (S)-2-phenylbutyl piperidinyl) 4853,4-dichlorobenzyl H H CH₂ (CH₂)₂(1-piperidinyl) (S)-2-phenylbutyl 4863,4-dichlorobenzoyl H H CH₂ (CH₂)₂(1-piperidinyl) 2-cyclopropylbutyl 4876-chloro-2-naphthoyl H H CH₂ (CH₂)₂NH₂ 2-cyclopropylbutyl 4886-chloro-2-naphthoyl H H CH₂ (CH₂)₂(1-piperidinyl) 2-cyclopropylbutyl489 3,4-dichlorobenzoyl H H CH₂ (CH₂)₂N[—CO(CH₂)₂CO—] (S)-2-phenylbutyl490 6-chloro-2-naphthoyl H H CH₂ (CH₂)₃NHCONH₂ (S)-2-phenylbutyl 4913,4-dichlorobenzoyl H H CH₂ (CH₂)₂NHCH(Me)CF₃ (S)-2-phenylbutyl 4923,4-dichlorobenzoyl H H CH₂ CH₂CH₂N[—COC(Me)₂CH₂CO—] (S)-2-phenylbutyl493 6-chloro-2-naphthoyl H H CH₂ (CH₂)₂N[—(CH₂)₆—] (S)-2-phenylbutyl 4946-chloro-2-naphthoyl H H CH₂ (CH₂)₂NHCONHiPr (S)-2-phenylbutyl 4954-biphenyl carboxylic H H CH₂ (CH₂)₂(1-piperidinyl) (S)-2-phenylbutyl496 2-phenylthiazole-4- H H CH₂ (CH₂)₂(1-piperidinyl) (S)-2-phenylbutylcarbonyl 497 4-chloro-biphenyl-2- H H CH₂ (CH₂)₂(1-piperidinyl)(S)-2-phenylbutyl carbonyl 498 6-chloro-2-naphthoyl H H CH₂(CH₂)₂N(Ac)iPr (S)-2-phenylbutyl 499 6-chloro-2-naphthoyl H H CH₂CH₂NHiPr (S)-2-phenylbutyl 500 6-chloro-2-naphthoyl H H CH₂CH₂NC(═NH)NH₂ (S)-2-phenylbutyl 510 2,4- H H CH₂ (CH₂)₂(1-piperidinyl)(S)-2-phenylbutyl dichlorophenylacetyl 502 3,4-dichlorobenzoyl H H CH₂(CH₂)₂NH₂ 2,4-dichlorobenzyl 503 3,4-dichlorobenzoyl H H CH₂(CH₂)₂(1-piperidinyl) 2,4-dichlorobenzyl 504 3,4-dichlorobenzoyl H H CH₂(CH₂)₂NHSO₂Me 2,4-dichlorobenzyl 505 3,4-dichlorobenzoyl H H CH₂(CH₂)₂NHSO₂(4-Me-Ph) 2,4-dichlorobenzyl 506 3,4-dichlorobenzoyl H H CH₂(S)—(CH₂)₂NHCO—CH(iPr)NH₂ 2,4-dichlorobenzyl 507 6-chloro-2-naphthoyl HH CH₂ (CH₂)₂NH₂ 2,4-dichlorobenzyl 508 6-chloro-2-naphthoyl H H CH₂(CH₂)₂(1-piperidinyl) 2,4-dichlorobenzyl 509 6-chloro-2-naphthoyl H HCH₂ (CH₂)₂NH₂ 2-(3-thienyl)butyl 510 6-chloro-2-naphthoyl H H CH₂(CH₂)₂(1-piperidinyl) (R)-2-(3-thienyl)butyl 511 6-chloro-2-naphthoyl HH CH₂ (CH₂)₂(1-piperidinyl) (S)-2-(3-thienyl)butyl 5126-chloro-2-naphthoyl H H CH₂ (CH₂)₂NH₂ 2-ethyl-2-methylbutyl 5136-chloro-2-naphthoyl H H CH₂ (CH₂)₂(1-piperidinyl) 2-ethyl-2-methylbutyl514 6-chloro-2-naphthoyl H H CH₂ (CH₂)₂(4-morpholinyl) 2,2-diphenylethyl515 6-chloro-2-naphthoyl H H CH₂ (CH₂)₂(4-morpholinyl) (S)-2-phenylbutyl516 6-chloro-2-naphthoyl H H CH₂ (CH₂)₂(4-morpholinyl)3,5-dichlorobenzyl 517 3,4-dichlorobenzoyl H H CH₂ (CH₂)₂(4-morpholinyl)3,5-dichlorobenzyl 518 (4-chloro- H H CH₂ (CH₂)₂(1-piperidinyl)(S)-2-phenylbutyl benzyl)NHCO 519 3,4-dichlorobenzyl + Ac H CH₂(CH₂)₂(1-piperidinyl) (S)-2-phenylbutyl MeCO 520 3,4-dichlorobenzoyl H HCH₂ (CH₂)₂NH₂ 2-ethyl-2-methylbutyl 521 3,4-dichlorobenzoyl H H CH₂(CH₂)₂(1-piperidinyl) 2-ethyl-2-methylbutyl 522 6-chloro-2-naphthoyl H HCH₂ (CH₂)₂(1-piperidinyl) 2,3,5-trichlorobenzyl 523 6-chloro-2-naphthoylH H CH₂ (CH₂)₂NHSO₂iPr (S)-2-phenylbutyl 524 6-chloro-2-naphthoyl H HCH₂ (CH₂)₂NHCO₂nBu (S)-2-phenylbutyl 525 6-chloro-2-naphthoyl H H CH₂1-iPr-4-piperidinyl (S)-2-phenylbutyl 526 6-chloro-2-naphthoyl H H CH₂(CH₂)₂(1-piperidinyl) (R)-2-phenylbutyl 527 5-(4-chlorophenyl)- H H CH₂(CH₂)₂(1-piperidinyl) 3,5-dichlorobenzyl isoxazole-3-carbonyl 5282,4-dichlorobenzoyl H H CH₂ (CH₂)₂(1-piperidinyl) 3,5-dichlorobenzyl 5296-methoxy-2- H H CH₂ (CH₂)₂(1-piperidinyl) 3,5-dichlorobenzyl naphthoyl530 6-chloro-2-naphthoyl H H ¹³CH₂ (CH₂)₂(1-piperidinyl)(S)-2-phenylbutyl 531 1-methoxy-2-napthoyl H H CH₂ (CH₂)₂(1-piperidinyl)3,5-dichlorobenzyl 532 4-(trifluoro- H H CH₂ (CH₂)₂(1-piperidinyl)3,5-dichlorobenzyl methoxy)cinnamoyl 533 5-(4-chlorophenyl)- H H CH₂(CH₂)₂(1-piperidinyl) (S)-2-phenylbutyl isoxazole-3-carbonyl 5342,4-dichlorobenzoyl H H CH₂ (CH₂)₂(1-piperidinyl) (S)-2-phenylbutyl 5354,5-dichlorophthaloyl R1 H CH₂ (CH₂)₂(1-piperidinyl) 3,5-dichlorobenzyl536 3-fluoro-4-(trifluoro- H H CH₂ (CH₂)₂(1-piperidinyl)3,5-dichlorobenzyl methoxy)cinnamoyl 537 6-methoxy-2- H H CH₂(CH₂)₂(1-piperidinyl) (S)-2-phenylbutyl naphthoyl 5381-methoxy-2-napthoyl H H CH₂ (CH₂)₂(1-piperidinyl) (S)-2-phenylbutyl 5393-fluoro-4-(trifluoro- H H CH₂ (CH₂)₂(1-piperidinyl) (S)-2-phenylbutylmethoxy)cinnamoyl 540 6-chloro-2-naphthoyl H H CD₂ (CH₂)₂(1-piperidinyl)(S)-2-phenylbutyl

TABLE 2 Synthesis of Compounds Conversion Scheme 1: of A to Cpd. Routeto A VN(R²)—Y—CO₂H P²NH—CH(U)—CO₂H Product U modification 14 Scheme 12-naphthoic-Gly- Fmoc-L-Arg(Pbf)-OH Scheme 3 P3 deprotection OH 25Scheme 1 Boc-Gly-OH Cbz-L-Asp[(NMe)OMe-OH Scheme 4 reduction to aldehydethen reductive amination 31 Scheme 1 Cbz-Gly-OH Fmoc-L-Dab(Boc)-OHScheme 4 P3 deprotection 33 Scheme 1 Cbz-Gly-OH Fmoc-L-Dab(Boc)-OHScheme 4 P3 deprotection then dialkylation with alkyl dibromide 37Scheme 1 Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4 P3 deprotection 38Scheme 1 Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4 P3 deprotection thendialkylation with alkyl dibromide 38 Scheme 1 2-naphthoic-Gly-Fmoc-L-Dab(Boc)-OH Scheme 3 P3 deprotection OH then dialkylation withalkyl dibromide 39 Scheme 1 Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4 P3deprotection then dialkylation with alkyl dibromide 49 Scheme 1Alloc-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4 P3 deprotection 50 Scheme 1Alloc-Gly-OH Boc-L-Arg(Fmoc)₂-OH Scheme 4 P3 deprotection 54 Scheme 1Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4 P3 deprotection 60 Scheme 1Cbz-Sar Fmoc-L-Orn(Boc)-OH Scheme 4 P3 deprotection 62 Scheme 1Cbz-Gly-OH Fmoc-L-Orn(Boc)-OH Scheme 3 P1 deprotect, R1 acylate, ringmethylate, P3 deprotect 63 Scheme 2 Boc-Gly-OH H-L-Orn(Cbz)-OallylScheme 4 P3 deprotection 63 Scheme 1 2-naphthoic-Gly- Fmoc-L-Orn(Boc)-OHScheme 3 P3 deprotection OH 64 Scheme 1 2-naphthoic-Gly-Fmoc-L-Orn(Boc)-OH Scheme 3 P3 deprotection OH then dialkylation withalkyl dibromide 65 Scheme 1 2-naphthoic-Gly- Fmoc-L-Orn(Boc)-OH Scheme 3P3 deprotection, OH reductive alkylation 67 Scheme 1 2-naphthoic-Gly-Fmoc-L-Orn(Boc)-OH Scheme 3 P3 deprotection, OH guanylation 79 Scheme 1Alloc-β-(2- Boc-L-Arg-(Cbz)₂-OH Scheme 4 P3 deprotection naphthyl)-L-Ala81 Scheme 1 Alloc-β-(2- Boc-L-Arg-(Cbz)₂-OH Scheme 4 P3 deprotectionnaphthyl)-L-Ala 83 Scheme 1 Alloc-β-(2- Boc-L-Arg-(Cbz)₂-OH Scheme 4 P3deprotection naphthyl)-L-Ala 85 Scheme 1 Alloc-β-(2- Boc-L-Arg-(Cbz)₂-OHScheme 4 P3 deprotection naphthyl)-L-Ala 86 Scheme 1 Alloc-β-(2-Boc-L-Arg-(Cbz)₂-OH Scheme 4 P3 deprotection naphthyl)-L-Ala 87 Scheme 1Alloc-β-(2- Boc-L-Arg-(Cbz)₂-OH Scheme 4 P3 deprotection naphthyl)-L-Ala105 Scheme 2 Boc-Gly-OH H-L-Orn(Cbz)-Oallyl Scheme 5 P3 deprotection,guanidinylation, deprotection 105 Scheme 2 Boc-Gly-OHH-L-Arg(Cbz)₂-Oallyl Scheme 4 P3 deprotection 105 Scheme 1 Alloc-Gly-OHBoc-L-Arg(Fmoc)₂-OH Scheme 4 P3 deprotection 105 Scheme 12-naphthoic-Gly- Fmoc-L-Arg(Pbf)-OH Scheme 3 P3 deprotection OH 106Scheme 2 Boc-Gly-OH H-L-Orn(Cbz)-Oallyl Scheme 4 P3 deprotection 107Scheme 2 Boc-Gly-OH H-L-Orn(Cbz)-Oallyl Scheme 4 P3 deprotection 108Scheme 2 Boc-Gly-OH H-L-Orn(Cbz)-Oallyl Scheme 5 P3 deprotection,guanidinylation, deprotection 109 Scheme 2 Boc-Gly-OHH-L-Orn(Cbz)-Oallyl Scheme 5 P3 deprotection, guanidinylation,deprotection 110 Scheme 2 Boc-Gly-OH H-L-Orn(Cbz)-Oallyl Scheme 5 P3deprotection, guanidinylation, deprotection 111 Scheme 2 Boc-Gly-OHH-L-Arg(Cbz)₂-Oallyl Scheme 4 P3 deprotection 112 Scheme 2 Boc-Gly-OHH-L-Arg(Cbz)₂-Oallyl Scheme 4 P3 deprotection 113 Scheme 2 Boc-Gly-OHH-L-Arg(Cbz)₂-Oallyl Scheme 4 P3 deprotection 114 Scheme 2 Boc-Gly-OHH-L-Arg(Cbz)₂-Oallyl Scheme 4 P3 deprotection 115 Scheme 2 Boc-Gly-OHH-L-Arg(Cbz)₂-Oallyl Scheme 4 P3 deprotection 116 Scheme 2 Boc-Gly-OHH-L-Arg(Cbz)₂-Oallyl Scheme 4 P3 deprotection 117 Scheme 2 Boc-Gly-OHBoc-L-Lys(Cbz)-OH Scheme 4 P3 deprotection 118 Scheme 2 Boc-Gly-OHBoc-L-Lys(Cbz)-OH Scheme 4 P3 deprotection 119 Scheme 2 Boc-Gly-OHBoc-L-Lys(Cbz)-OH Scheme 4 P3 deprotection 120 Scheme 2 Boc-Gly-OHBoc-L-Lys(Cbz)-OH Scheme 4 P3 deprotection 121 Scheme 2 Boc-Gly-OHBoc-L-Lys(Cbz)-OH Scheme 4 P3 deprotection 122 Scheme 2 Boc-Gly-OHBoc-L-Lys(Cbz)-OH Scheme 4 P3 deprotection 123 Scheme 2 Boc-Gly-OHBoc-L-Lys(Cbz)-OH Scheme 4 P3 deprotection 124 Scheme 2 Boc-Gly-OHBoc-L-Lys(Cbz)-OH Scheme 4 P3 deprotection 125 Scheme 2 Boc-Gly-OHBoc-L-Lys(Cbz)-OH Scheme 4 P3 deprotection 126 Scheme 2 Boc-Gly-OHBoc-L-Lys(Cbz)-OH Scheme 4 P3 deprotection 127 Scheme 2 Boc-Gly-OHBoc-L-Lys(Cbz)-OH Scheme 4 P3 deprotection 128 Scheme 2 Boc-Gly-OHBoc-L-Lys(Cbz)-OH Scheme 4 P3 deprotection 129 Scheme 2 Boc-Gly-OHBoc-L-Lys(Cbz)-OH Scheme 4 P3 deprotection 130 Scheme 2 Boc-Gly-OHH-L-Arg(Cbz)₂-Oallyl Scheme 4 P3 deprotection 131 Scheme 2 Boc-Gly-OHH-L-Arg(Cbz)₂-Oallyl Scheme 4 P3 deprotection 132 Scheme 2 Boc-Gly-OHH-L-Arg(Cbz)₂-Oallyl Scheme 4 P3 deprotection 133 Scheme 2 Boc-Gly-OHH-L-Arg(Cbz)₂-Oallyl Scheme 4 P3 deprotection 134 Scheme 2 Boc-Gly-OHH-L-Arg(Cbz)₂-Oallyl Scheme 4 P3 deprotection 135 Scheme 2 Boc-Gly-OHH-L-Arg(Cbz)₂-Oallyl Scheme 4 P3 deprotection 136 Scheme 2 Boc-Gly-OHH-L-Arg(Cbz)₂-Oallyl Scheme 4 P3 deprotection 137 Scheme 2 Boc-Gly-OHH-L-Arg(Cbz)₂-Oallyl Scheme 4 P3 deprotection 138 Scheme 2 Boc-Gly-OHH-L-Arg(Cbz)₂-Oallyl Scheme 4 P3 deprotection 139 Scheme 2 Boc-Gly-OHH-L-Arg(Cbz)₂-Oallyl Scheme 4 P3 deprotection 140 Scheme 2 Boc-Gly-OHH-L-Arg(Cbz)₂-Oallyl Scheme 4 P3 deprotection 141 Scheme 2 Boc-Gly-OHH-L-Arg(Cbz)₂-Oallyl Scheme 4 P3 deprotection 142 Scheme 2 Boc-Gly-OHH-L-Arg(Cbz)₂-Oallyl Scheme 4 P3 deprotection 143 Scheme 2 Boc-Gly-OHH-L-Arg(Cbz)₂-Oallyl Scheme 4 P3 deprotection 144 Scheme 2 Boc-Gly-OHH-L-Arg(Cbz)₂-Oallyl Scheme 4 P3 deprotection 145 Scheme 2 Boc-Gly-OHH-L-Arg(Cbz)₂-Oallyl Scheme 4 P3 deprotection 146 Scheme 2 Boc-Gly-OHH-L-Arg(Cbz)₂-Oallyl Scheme 4 P3 deprotection 147 Scheme 2 Boc-Gly-OHH-L-Arg(Cbz)₂-Oallyl Scheme 4 P3 deprotection 148 Scheme 2 Boc-Gly-OHH-L-Arg(Cbz)₂-Oallyl Scheme 4 P3 deprotection 149 Scheme 2 Boc-Gly-OHH-L-Arg(Cbz)₂-Oallyl Scheme 4 P3 deprotection 150 Scheme 2 Boc-Gly-OHH-L-Arg(Cbz)₂-Oallyl Scheme 4 P3 deprotection 151 Scheme 1 Alloc-Gly-OHBoc-L-Arg(Fmoc)₂-OH Scheme 4 P3 deprotection 152 Scheme 1 Alloc-Gly-OHBoc-L-Arg(Fmoc)₂-OH Scheme 4 P3 deprotection 153 Scheme 1 Alloc-Gly-OHBoc-L-Arg(Fmoc)₂-OH Scheme 4 P3 deprotection 154 Scheme 1 Alloc-Gly-OHBoc-L-Arg(Fmoc)₂-OH Scheme 4 P3 deprotection 155 Scheme 1 Alloc-Gly-OHBoc-L-Arg(Fmoc)₂-OH Scheme 4 P3 deprotection 156 Scheme 1 Alloc-Gly-OHBoc-L-Arg(Fmoc)₂-OH Scheme 4 P3 deprotection 157 Scheme 1 Alloc-Gly-OHBoc-L-Arg(Fmoc)₂-OH Scheme 4 P3 deprotection 158 Scheme 1 Alloc-Gly-OHBoc-L-Arg(Fmoc)₂-OH Scheme 4 P3 deprotection 159 Scheme 1 Alloc-Gly-OHBoc-L-Arg(Fmoc)₂-OH Scheme 4 P3 deprotection 160 Scheme 1 Alloc-Gly-OHBoc-L-Arg(Fmoc)₂-OH Scheme 4 P3 deprotection 161 Scheme 1 Alloc-Gly-OHBoc-L-Arg(Fmoc)₂-OH Scheme 4 P3 deprotection 162 Scheme 1 Alloc-Gly-OHBoc-L-Arg(Fmoc)₂-OH Scheme 4 P3 deprotection 163 Scheme 1 Alloc-Gly-OHBoc-L-Arg(Fmoc)₂-OH Scheme 4 P3 deprotection 164 Scheme 1 Alloc-Gly-OHBoc-L-Arg(Fmoc)₂-OH Scheme 4 P3 deprotection 165 Scheme 1 Alloc-Gly-OHBoc-L-Arg(Fmoc)₂-OH Scheme 4 P3 deprotection 166 Scheme 1 Alloc-Gly-OHBoc-L-Arg(Fmoc)₂-OH Scheme 4 P3 deprotection 167 Scheme 1 Alloc-Gly-OHBoc-L-Arg(Fmoc)₂-OH Scheme 4 P3 deprotection 168 Scheme 1 Alloc-Gly-OHBoc-L-Arg(Fmoc)₂-OH Scheme 4 P3 deprotection 169 Scheme 1 Alloc-Gly-OHBoc-L-Arg(Fmoc)₂-OH Scheme 4 P3 deprotection 170 Scheme 1 Alloc-Gly-OHBoc-L-Arg(Fmoc)₂-OH Scheme 4 P3 deprotection 171 Scheme 1 Alloc-Gly-OHBoc-L-Arg(Fmoc)₂-OH Scheme 4 P3 deprotection 172 Scheme 1 Alloc-Gly-OHBoc-L-Arg(Fmoc)₂-OH Scheme 4 P3 deprotection 173 Scheme 1 Alloc-Gly-OHBoc-L-Arg(Fmoc)₂-OH Scheme 4 P3 deprotection 174 Scheme 1 Alloc-Gly-OHBoc-L-Arg(Fmoc)₂-OH Scheme 4 P3 deprotection 175 Scheme 1 Alloc-Gly-OHBoc-L-Arg(Fmoc)₂-OH Scheme 4 P3 deprotection 176 Scheme 1 Alloc-Gly-OHBoc-L-Arg(Fmoc)₂-OH Scheme 4 P3 deprotection 177 Scheme 1 Alloc-Gly-OHBoc-L-Arg(Fmoc)₂-OH Scheme 4 P3 deprotection 178 Scheme 1 Alloc-Gly-OHBoc-L-Arg(Fmoc)₂-OH Scheme 4 P3 deprotection 179 Scheme 1 Alloc-Gly-OHBoc-L-Arg(Fmoc)₂-OH Scheme 4 P3 deprotection 180 Scheme 1 Alloc-Gly-OHBoc-L-Arg(Fmoc)₂-OH Scheme 4 P3 deprotection 181 Scheme 12-naphthoic-Gly- Fmoc-L-Arg(Pbf)-OH Scheme 3 P3 deprotection OH 182Scheme 1 2-naphthoic-Gly- Fmoc-L-Arg(Pbf)-OH Scheme 3 P3 deprotection OH183 Scheme 1 2-naphthoic-Gly- Fmoc-L-Arg(Pbf)-OH Scheme 3 P3deprotection OH 184 Scheme 1 Alloc-Gly-OH Boc-L-Arg(Fmoc)₂-OH Scheme 4P3 deprotection 185 Scheme 1 Alloc-Gly-OH Boc-L-Arg(Fmoc)₂-OH Scheme 4P3 deprotection 186 Scheme 1 Alloc-Gly-OH Boc-L-Arg(Fmoc)₂-OH Scheme 4P3 deprotection 187 Scheme 1 Alloc-Gly-OH Boc-L-Arg(Fmoc)₂-OH Scheme 4P3 deprotection 188 Scheme 1 Alloc-Gly-OH Boc-L-Arg(Fmoc)₂-OH Scheme 4P3 deprotection 189 Scheme 1 Alloc-Gly-OH Boc-L-Arg(Fmoc)₂-OH Scheme 4P3 deprotection 190 Scheme 1 Alloc-Gly-OH Boc-L-Arg(Fmoc)₂-OH Scheme 4P3 deprotection 191 Scheme 1 Alloc-Gly-OH Boc-L-Arg(Fmoc)₂-OH Scheme 4P3 deprotection 192 Scheme 1 Alloc-Gly-OH Boc-L-Arg(Fmoc)₂-OH Scheme 4P3 deprotection 193 Scheme 1 Alloc-Gly-OH Boc-L-Arg(Fmoc)₂-OH Scheme 4P3 deprotection 194 Scheme 1 Alloc-Gly-OH Boc-L-Arg(Fmoc)₂-OH Scheme 4P3 deprotection 195 Scheme 1 Alloc-Gly-OH Boc-L-Arg(Fmoc)₂-OH Scheme 4P3 deprotection 196 Scheme 1 2-naphthoic-Gly- Fmoc-α-(1-Boc-4- Scheme 3P3 deprotection OH piperidinyl)-DL-Gly-OH 197 Scheme 1 2-naphthoic-Gly-Fmoc-β-(1-Boc-4- Scheme 3 P3 deprotection OH piperidinyl)-DL-Ala-OH 198Scheme 1 Alloc-Gly-OH Boc-L-Arg(Fmoc)₂-OH Scheme 4 P3 deprotection 199Scheme 1 Alloc-Gly-OH Boc-L-Arg(Fmoc)₂-OH Scheme 4 P3 deprotection 200Scheme 1 2-naphthoic-Gly- Fmoc-L-Arg(Pbf)-OH Scheme 3 P3 deprotection OH201 Scheme 1 2-naphthoic-Gly- Fmoc-L-Arg(Pbf)-OH Scheme 3 P3deprotection OH 202 Scheme 1 2-naphthoic-Gly- Fmoc-L-Arg(Pbf)-OH Scheme3 P3 deprotection OH 203 Scheme 1 2-naphthoic-Gly- Fmoc-L-Arg(Pbf)-OHScheme 3 P3 deprotection OH 204 Scheme 1 2-naphthoic-Gly-Fmoc-L-Arg(Pbf)-OH Scheme 3 P3 deprotection OH 205 Scheme 12-naphthoic-Gly- Fmoc-L-Arg(Pbf)-OH Scheme 3 P3 deprotection OH 206Scheme 1 2-naphthoic-Gly- Fmoc-L-Arg(Pbf)-OH Scheme 3 P3 deprotection OH207 Scheme 1 Alloc-Gly-OH Boc-L-Arg(Fmoc)₂-OH Scheme 4 P3 deprotection208 Scheme 1 Alloc-Gly-OH Boc-L-Arg(Fmoc)₂-OH Scheme 4 P3 deprotection209 Scheme 1 Alloc-Gly-OH Boc-L-Arg(Fmoc)₂-OH Scheme 4 P3 deprotection210 Scheme 1 Alloc-Gly-OH Boc-L-Arg(Fmoc)₂-OH Scheme 4 P3 deprotection211 Scheme 1 Cbz-Gly-OH Fmoc-L-Orn(Boc)-OH Scheme 4 P3 deprotection 212Scheme 1 Cbz-Gly-OH Fmoc-L-Orn(Boc)-OH Scheme 4 P3 deprotection 213Scheme 1 Cbz-Gly-OH Fmoc-L-Orn(Boc)-OH Scheme 4 P3 deprotection 214Scheme 1 Alloc-Gly-OH Boc-L-Arg(Fmoc)₂-OH Scheme 4 P3 deprotection 215Scheme 1 2-naphthoic-Gly- Fmoc-L-Arg(NMe)₂Pbf-OH Scheme 3 P3deprotection OH 216 Scheme 1 Alloc-Gly-OH Boc-L-Arg(Fmoc)₂-OH Scheme 4P3 deprotection 217 Scheme 1 Alloc-Gly-OH Boc-L-Arg(Fmoc)₂-OH Scheme 4P3 deprotection 218 Scheme 1 Cbz-Gly-OH Fmoc-L-Orn(Boc)-OH Scheme 4 P3deprotection 219 Scheme 1 Cbz-Gly-OH Fmoc-L-Orn(Boc)-OH Scheme 4 P3deprotection 220 Scheme 1 Cbz-Gly-OH Fmoc-L-Orn(Boc)-OH Scheme 4 P3deprotection 221 Scheme 1 Cbz-Gly-OH Fmoc-L-Orn(Boc)-OH Scheme 4 P3deprotection 222 Scheme 1 Cbz-Gly-OH Fmoc-L-Orn(Boc)-OH Scheme 4 P3deprotection 223 Scheme 1 Cbz-Gly-OH Fmoc-L-Orn(Boc)-OH Scheme 4 P3deprotection 224 Scheme 1 Cbz-Gly-OH Fmoc-L-Orn(Boc)-OH Scheme 4 P3deprotection, guanidinylation 225 Scheme 1 2-naphthoic-Gly-Fmoc-L-Orn(Boc)-OH Scheme 3 P3 deprotection, OH reductive alkylation 226Scheme 1 2-naphthoic-Gly- Fmoc-L-Arg(Pbf)-OH Scheme 3 P3 deprotection OH227 Scheme 1 2-naphthoic-Gly- Fmoc-L-Arg(Pbf)-OH Scheme 3 P3deprotection OH 228 Scheme 1 Cbz-Gly-OH Fmoc-L-Orn(Boc)-OH Scheme 4 P3deprotection, reductive alkylation 229 Scheme 1 2-naphthoic-Gly-Fmoc-L-Lys(i-Pr)Fmoc- Scheme 3 P3 deprotection OH OH 230 Scheme 1Cbz-Gly-OH Fmoc-L-Orn(Boc)-OH Scheme 4 P3 deprotection 231 Scheme 1Cbz-Gly-OH Fmoc-L-Orn(Boc)-OH Scheme 4 P3 deprotection 232 Scheme 1Cbz-Gly-OH Fmoc-L-Orn(Boc)-OH Scheme 4 P3 deprotection 233 Scheme 1Cbz-Gly-OH Fmoc-L-Orn(Boc)-OH Scheme 4 P3 deprotection 234 Scheme 1Cbz-Gly-OH Fmoc-L-Orn(Boc)-OH Scheme 4 P3 deprotection 235 Scheme 1Cbz-Gly-OH Fmoc-L-Orn(Boc)-OH Scheme 4 P3 deprotection 236 Scheme 1Cbz-Gly-OH Fmoc-L-Orn(Boc)-OH Scheme 4 P3 deprotection 237 Scheme 1Cbz-Gly-OH Fmoc-L-Orn(Boc)-OH Scheme 4 P3 deprotection 238 Scheme 1Cbz-Gly-OH Fmoc-L-Orn(Boc)-OH Scheme 4 P3 deprotection 239 Scheme 1Cbz-Gly-OH Fmoc-L-Orn(Boc)-OH Scheme 4 P3 deprotection 240 Scheme 1Cbz-Gly-OH Fmoc-L-Orn(Boc)-OH Scheme 4 P3 deprotection 241 Scheme 1Cbz-Gly-OH Fmoc-L-Orn(Boc)-OH Scheme 4 P3 deprotection 242 Scheme 12-naphthoic-Gly- Fmoc-L-Arg(Pbf)-OH Scheme 3 P3 deprotection OH 243Scheme 1 2-naphthoic-Gly- Fmoc-L-Arg(Pbf)-OH Scheme 3 P3 deprotection OH244 Scheme 1 2-naphthoic-Gly- Fmoc-L-Arg(Pbf)-OH Scheme 3 P3deprotection OH 245 Scheme 1 2-naphthoic-Gly- Fmoc-L-Orn(Boc)-OH Scheme3 P3 deprotection, OH reductive alkylation 246 Scheme 1 2-naphthoic-Gly-Fmoc-L-Orn(Boc)-OH Scheme 3 P3 deprotection, OH reductive alkylation 247Scheme 1 2-naphthoic-Gly- Fmoc-L-Orn(Boc)-OH Scheme 3 P3 deprotection,OH reductive alkylation 248 Scheme 1 2-naphthoic-Gly- Fmoc-L-Orn(Boc)-OHScheme 3 P3 deprotection, OH reductive alkylation 249 Scheme 12-naphthoic-Gly- Fmoc-L-Arg(Pbf)-OH Scheme 3 P3 deprotection OH 250Scheme 1 2-naphthoic-Gly- Fmoc-L-Arg(Pbf)-OH Scheme 3 P3 deprotection OH251 Scheme 1 2-naphthoic-Gly- Fmoc-L-Arg(Pbf)-OH Scheme 3 P3deprotection OH 252 Scheme 1 Cbz-Gly-OH Fmoc-L-Orn(Boc)-OH Scheme 4 P3deprotection 253 Scheme 1 Cbz-Gly-OH Fmoc-L-Orn(Boc)-OH Scheme 4 P3deprotection 254 Scheme 1 Cbz-Gly-OH Fmoc-L-Orn(Boc)-OH Scheme 4 P3deprotection 255 Scheme 1 Cbz-Gly-OH Fmoc-L-Orn(Boc)-OH Scheme 4 P1deprotect, R1 acylate, ring methylate, P3 deprotect 256 Scheme 1Cbz-Gly-OH Fmoc-L-Orn(Boc)-OH Scheme 4 P3 deprotection 257 Scheme 1Cbz-Gly-OH Fmoc-L-Orn(Boc)-OH Scheme 4 P3 deprotection 258 Scheme 1Cbz-Gly-OH Fmoc-L-Orn(Boc)-OH Scheme 4 P3 deprotection then dialkylationwith alkyl dibromide 259 Scheme 1 Cbz-Gly-OH Fmoc-L-Orn(Boc)-OH Scheme 4P3 deprotection then dialkylation with alkyl dibromide 259 Scheme 1Boc-Gly-OH Fmoc-L-Orn(Cbz)-OH Scheme 5 P3 deprotection, dialkylation 260Scheme 1 2-naphthoic-Gly- Fmoc-L-Dab(Boc)-OH Scheme 3 P3 deprotection OH260 Scheme 1 Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4 P3 deprotection 261Scheme 1 2-naphthoic-Gly- Fmoc-L-Orn(Boc)-OH Scheme 3 P3 deprotection OHthen dialkylation with alkyl dibromide 262 Scheme 1 2-naphthoic-Gly-Fmoc-L-Orn(Boc)-OH Scheme 3 P3 deprotection OH then dialkylation withalkyl dibromide 263 Scheme 1 2-naphthoic-Gly- Fmoc-L-Arg(Pbf)-OH Scheme3 P3 deprotection OH 264 Scheme 1 2-naphthoic-Gly- Fmoc-L-Arg(Pbf)-OHScheme 3 P3 deprotection OH 265 Scheme 1 2-naphthoic-Gly-Fmoc-L-Arg(Pbf)-OH Scheme 3 P3 deprotection OH 266 Scheme 1 Cbz-Gly-OHFmoc-L-Orn(Boc)-OH Scheme 4 P3 deprotection then dialkylation with alkyldibromide 267 Scheme 1 Cbz-Gly-OH Fmoc-L-Orn(Boc)-OH Scheme 4 P3deprotection then dialkylation with alkyl dibromide 268 Scheme 1Cbz-Gly-OH Fmoc-L-Orn(Boc)-OH Scheme 4 P3 deprotection then dialkylationwith alkyl dibromide 269 Scheme 1 2-naphthoic-Gly- Fmoc-L-Arg(Pbf)-OHScheme 3 P3 deprotection OH 270 Scheme 1 2-naphthoic-Gly-Fmoc-L-Arg(Pbf)-OH Scheme 3 P3 deprotection OH 271 Scheme 1 Cbz-Gly-OHFmoc-L-Dap(Boc)-OH Scheme 4 P3 deprotection 272 Scheme 1 Cbz-Gly-OHFmoc-L-Dap(Boc)-OH Scheme 4 P3 deprotection 273 Scheme 1 Cbz-Gly-OHBoc-L-Dab(Fmoc)-OH Scheme 4 P3 deprotection 273 Scheme 1 Cbz-Gly-OHFmoc-L-Dab(Boc)-OH Scheme 4 P3 deprotection 274 Scheme 1 Cbz-Gly-OHBoc-L-Dab(Fmoc)-OH Scheme 4 P3 deprotection 274 Scheme 1 Cbz-Gly-OHFmoc-L-Dab(Boc)-OH Scheme 4 P3 deprotection 275 Scheme 1 Cbz-Gly-OHFmoc-L-Dap(Boc)-OH Scheme 4 P3 deprotection then dialkylation with alkyldibromide 276 Scheme 1 Cbz-Gly-OH Fmoc-L-Dap(Boc)-OH Scheme 4 P3deprotection then dialkylation with alkyl dibromide 276 Scheme 1Cbz-Gly-OH Fmoc-L-Dap(Boc)-OH Scheme 5 P3 deprotection then dialkylationwith alkyl dibromide 277 Scheme 1 Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4P3 deprotection 278 Scheme 1 Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4 P3deprotection 279 Scheme 1 Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4 P3deprotection 280 Scheme 1 Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4 P3deprotection 281 Scheme 1 Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4 P3deprotection then dialkylation with alkyl dibromide 282 Scheme 1Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4 P3 deprotection then dialkylationwith alkyl dibromide 283 Scheme 1 Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4P3 deprotection then dialkylation with alkyl dibromide 284 Scheme 1Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4 P3 deprotection then dialkylationwith alkyl dibromide 285 Scheme 1 Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4P3 deprotection then dialkylation with alkyl dibromide 286 Scheme 12-naphthoic-Gly- Fmoc-L-Arg(Pbf)-OH Scheme 3 P3 deprotection OH 287Scheme 1 2-naphthoic-Gly- Fmoc-L-Arg(Pbf)-OH Scheme 3 P3 deprotection OH288 Scheme 1 2-naphthoic-Gly- Fmoc-L-Arg(Pbf)-OH Scheme 3 P3deprotection OH 289 Scheme 1 2-naphthoic-Gly- Fmoc-L-Arg(Pbf)-OH Scheme3 P3 deprotection OH 290 Scheme 1 2-naphthoic-Gly- Fmoc-L-Arg(Pbf)-OHScheme 3 P3 deprotection OH 291 Scheme 1 2-naphthoic-Gly-Fmoc-L-Arg(Pbf)-OH Scheme 3 P3 deprotection OH 292 Scheme 12-naphthoic-Gly- Fmoc-L-Arg(Pbf)-OH Scheme 3 P3 deprotection OH 293Scheme 1 Cbz-Gly-OH Fmoc-L-Orn(Boc)-OH Scheme 4 P3 deprotection thenacylation 294 Scheme 1 Cbz-Gly-OH Fmoc-L-Orn(Boc)-OH Scheme 4 P3deprotection then acylation 295 Scheme 1 2-naphthoic-Gly-Fmoc-L-Arg(Pbf)-OH Scheme 3 P3 deprotection OH 296 Scheme 12-naphthoic-Gly- Fmoc-L-Arg(Pbf)-OH Scheme 3 P3 deprotection OH 297Scheme 1 2-naphthoic-Gly- Fmoc-L-Arg(Pbf)-OH Scheme 3 P3 deprotection OH298 Scheme 1 2-naphthoic-Gly- Fmoc-L-Arg(Pbf)-OH Scheme 3 P3deprotection OH 299 Scheme 1 Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4 P3deprotection then acylation 300 Scheme 1 Cbz-Gly-OH Fmoc-L-Dab(Boc)-OHScheme 4 P3 deprotection then acylation 301 Scheme 1 Cbz-β-AlaFmoc-L-Dab(Boc)-OH Scheme 4 P3 deprotection 302 Scheme 1 Cbz-β-AlaFmoc-L-Dab(Boc)-OH Scheme 4 P3 deprotection 303 Scheme 1 Cbz-β-AlaFmoc-L-Dab(Boc)-OH Scheme 4 P3 deprotection 304 Scheme 1 Cbz-β-AlaFmoc-L-Dab(Boc)-OH Scheme 4 P3 deprotection then dialkylation with alkyldibromide 305 Scheme 1 Cbz-β-Ala Fmoc-L-Dab(Boc)-OH Scheme 4 P3deprotection then dialkylation with alkyl dibromide 306 Scheme 1Cbz-β-Ala Fmoc-L-Dab(Boc)-OH Scheme 4 P3 deprotection then dialkylationwith alkyl dibromide 307 Scheme 1 2-naphthoic-Gly- Fmoc-L-Arg(Pbf)-OHScheme 3 R5 deprotection OH and amidation then P3 deprotection 308Scheme 1 Alloc-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4 P3 deprotection 309Scheme 1 Alloc-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4 P3 deprotection 310Scheme 1 2-naphthoic-Gly- Fmoc-L-Arg(Pbf)-OH Scheme 3 P3 deprotection OH311 Scheme 1 2-naphthoic-Gly- Fmoc-L-Arg(Pbf)-OH Scheme 3 P3deprotection OH 312 Scheme 1 2-naphthoic-Gly- Fmoc-L-Orn(Boc)-OH Scheme3 P3 deprotection OH 313 Scheme 1 2-naphthoic-Gly- Fmoc-L-Orn(Boc)-OHScheme 3 P3 deprotection OH 314 Scheme 1 2-naphthoic-Gly-Fmoc-L-Orn(Boc)-OH Scheme 3 P3 deprotection OH 315 Scheme 12-naphthoic-Gly- Fmoc-L-Orn(Boc)-OH Scheme 3 P3 deprotection OH 316Scheme 1 2-naphthoic-Gly- Fmoc-L-Orn(Boc)-OH Scheme 3 P3 deprotection OH317 Scheme 1 2-naphthoic-Gly- Fmoc-L-Orn(Boc)-OH Scheme 3 P3deprotection OH 318 Scheme 1 2-naphthoic-Gly- Fmoc-L-Orn(Boc)-OH Scheme3 P3 deprotection OH 319 Scheme 1 2-naphthoic-Gly- Fmoc-L-Orn(Boc)-OHScheme 3 P3 deprotection OH 320 Scheme 1 2-naphthoic-Gly-Fmoc-L-Orn(Boc)-OH Scheme 3 P3 deprotection OH 321 Scheme 12-naphthoic-Gly- Fmoc-L-Orn(Boc)-OH Scheme 3 P3 deprotection OH 322Scheme 1 2-naphthoic-Gly- Fmoc-L-Orn(Boc)-OH Scheme 3 P3 deprotection OH323 Scheme 1 2-naphthoic-Gly- Fmoc-L-Orn(Boc)-OH Scheme 3 P3deprotection OH 324 Scheme 1 2-naphthoic-Gly- Fmoc-L-Orn(Boc)-OH Scheme3 P3 deprotection OH 325 Scheme 1 2-naphthoic-Gly- Fmoc-L-Orn(Boc)-OHScheme 3 P3 deprotection OH 326 Scheme 1 Alloc-Gly-OH Fmoc-L-Dab(Boc)-OHScheme 4 P3 deprotection then dialkylation with alkyl dibromide 327Scheme 1 Alloc-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4 P3 deprotection thendialkylation with alkyl dibromide 328 Scheme 1 Alloc-Gly-OHFmoc-L-Dab(Boc)-OH Scheme 4 P3 deprotection then dialkylation with alkyldibromide 329 Scheme 1 Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4 P3deprotection 330 Scheme 1 Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4 P3deprotection 331 Scheme 1 Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 5 P3deprotection then dialkylation with alkyl dibromide 331 Scheme 1Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4 P3 deprotection then dialkylationwith alkyl dibromide 332 Scheme 1 Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 5P3 deprotection then dialkylation with alkyl dibromide 333 Scheme 1Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 5 P3 deprotection then dialkylationwith alkyl dibromide 334 Scheme 1 Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4P3 deprotection 335 Scheme 1 Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4 P3deprotection 336 Scheme 1 Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4 P3deprotection 337 Scheme 1 Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4 P3deprotection 338 Scheme 1 Cbz-Gly-OH Fmoc-L-Dap(Boc)-OH Scheme 5 P3deprotection then dialkylation with alkyl dibromide 339 Scheme 1Cbz-Gly-OH Fmoc-L-Dap(Boc)-OH Scheme 4 P3 deprotection then dialkylationwith alkyl dibromide 340 Scheme 1 2-naphthoic-Gly- Fmoc-L-Orn(Boc)-OHScheme 3 P3 deprotection OH 341 Scheme 1 2-naphthoic-Gly-Fmoc-L-Orn(Boc)-OH Scheme 3 P3 deprotection OH 342 Scheme 12-naphthoic-Gly- Fmoc-L-Orn(Boc)-OH Scheme 3 P3 deprotection OH thendialkylation with alkyl dibromide 343 Scheme 1 2-naphthoic-Gly-Fmoc-L-Arg(Pbf)-OH Scheme 3 R5 deprotection OH and amidation then P3deprotection 344 Scheme 1 2-naphthoic-Gly- Fmoc-L-Arg(Pbf)-OH Scheme 3R5 deprotection OH and amidation then P3 deprotection 345 Scheme 1Cbz-Gly-OH Fmoc-L-Dap(Boc)-OH Scheme 4 P3 deprotection, alkylation 346Scheme 1 Cbz-Gly-OH Fmoc-L-Dap(Boc)-OH Scheme 4 P3 deprotection,dialkylation 347 Scheme 1 Alloc-Gly-OH Fmoc-L-Dap(Boc)-OH Scheme 4 P3deprotection 348 Scheme 1 Alloc-Gly-OH Fmoc-L-Dap(Boc)-OH Scheme 4 P3deprotection 349 Scheme 1 Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4 P3deprotection 350 Scheme 1 Cbz-Gly-OH Fmoc-L-Dap(Boc)-OH Scheme 5 P3deprotection then dialkylation with alkyl dibromide 350 Scheme 1Cbz-Gly-OH Fmoc-L-Dap(Boc)-OH Scheme 4 P3 deprotection then dialkylationwith alkyl dibromide 351 Scheme 1 Cbz-Gly-OH Fmoc-L-Dap(Boc)-OH Scheme 5P3 deprotection then dialkylation with alkyl dibromide 352 Scheme 1Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4 P3 deprotection 353 Scheme 1Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4 P3 deprotection 354 Scheme 1Alloc-Gly-OH Fmoc-L-Dap(Boc)-OH Scheme 5 P3 deprotection thendialkylation with alkyl dibromide 355 Scheme 1 Alloc-Gly-OHFmoc-L-Dap(Boc)-OH Scheme 5 P3 deprotection then dialkylation with alkyldibromide 356 Scheme 1 2-naphthoic-Gly- Fmoc-L-Orn(Boc)-OH Scheme 3 P3deprotection OH 357 Scheme 1 2-naphthoic-Gly- Fmoc-L-Orn(Boc)-OH Scheme3 P3 deprotection OH 358 Scheme 1 2-naphthoic-Gly-Cbz-L-Asp[N(Me)OMe]-OH Scheme 3 P3 conversion to OH aldehyde thenreductive amination 359 Scheme 1 Cbz-Gly-OH Fmoc-L-Orn(Boc)-OH Scheme 4P3 deprotection then dialkylation with alkyl dibromide 360 Scheme 12-naphthoic-Gly- Fmoc-L-Orn(Boc)-OH Scheme 3 P3 deprotection OH 361Scheme 1 Boc-Gly-OH Cbz-L-Asp[N(Me)OMe]-OH Scheme 4 P3 conversion toaldehyde then reductive amination 362 Scheme 1 Boc-Gly-OHCbz-L-Asp[N(Me)OMe]-OH Scheme 4 P3 conversion to aldehyde then reductiveamination 363 Scheme 1 Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4 P3deprotection then dialkylation with alkyl dibromide 364 Scheme 1Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4 P3 deprotection then dialkylationwith alkyl dibromide 365 Scheme 1 Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4P3 deprotection then dialkylation with alkyl dibromide 366 Scheme 1Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4 P3 deprotection 367 Scheme 1Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4 P3 deprotection then dialkylationwith alkyl dibromide 368 Scheme 1 Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4P3 deprotection then dialkylation with alkyl dibromide 369 Scheme 1Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4 P3 deprotection 370 Scheme 1Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4 P3 deprotection 371 Scheme 1Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4 P3 deprotection 372 Scheme 1Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 5 P3 deprotection then dialkylationwith alkyl dibromide 373 Scheme 1 Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 5P3 deprotection then dialkylation with alkyl dibromide 374 Scheme 1Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 5 P3 deprotection then dialkylationwith alkyl dibromide 375 Scheme 1 Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4P3 deprotection 376 Scheme 1 Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4 P3deprotection 377 Scheme 1 Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4 P3deprotection 378 Scheme 1 Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4 P3deprotection then dialkylation with alkyl dibromide 379 Scheme 1Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4 P3 deprotection then dialkylationwith alkyl dibromide 380 Scheme 1 Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4P3 deprotection then dialkylation with alkyl dibromide 381 Scheme 1Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4 P3 deprotection, alkylation 382Scheme 1 Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4 P3 deprotection,alkylation 383 Scheme 1 Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4 P3deprotection, alkylation 384 Scheme 1 2-naphthoic-Gly-Fmoc-L-Orn(Boc)-OH Scheme 3 P3 deprotection OH 385 Scheme 12-naphthoic-Gly- Fmoc-L-Orn(Boc)-OH Scheme 3 P3 deprotection OH 386Scheme 1 Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4 P3 deprotection thendialkylation with alkyl dibromide 387 Scheme 1 Cbz-Gly-OHFmoc-L-Dab(Boc)-OH Scheme 4 P3 deprotection, alkylation 388 Scheme 12-naphthoic-Gly- Fmoc-L-Dab(Boc)-OH Scheme 3 P3 deprotection OH 389Scheme 1 2-naphthoic-Gly- Fmoc-L-Dab(Boc)-OH Scheme 3 P3 deprotection OH390 Scheme 1 2-naphthoic-Gly- Fmoc-L-Orn(Boc)-OH Scheme 3 P3deprotection OH 391 Scheme 1 Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4 P3deprotection then dialkylation with alkyl dibromide 392 Scheme 1Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4 P3 deprotection 393 Scheme 1Cbz-Gly-OH Fmoc-L-Dap(Boc)-OH Scheme 4 P3 deprotection, acylation 394Scheme 1 2-naphthoic-Gly- Fmoc-L-Dab(Boc)-OH Scheme 3 P3 deprotection OHthen dialkylation with alkyl dibromide 395 Scheme 1 2-naphthoic-Gly-Fmoc-L-Dab(Boc)-OH Scheme 3 P3 deprotection OH then dialkylation withalkyl dibromide 396 Scheme 1 Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4 P3deprotection then dialkylation with alkyl dibromide 397 Scheme 1Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4 P3 deprotection 398 Scheme 1Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4 P3 deprotection then dialkylationwith alkyl dibromide 399 Scheme 1 Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4P3 deprotection 400 Scheme 1 Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4 P3deprotection then dialkylation with alkyl dibromide 401 Scheme 1Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4 P3 deprotection 402 Scheme 1Cbz-Gly-OH Fmoc-L-Dap(Boc)-OH Scheme 4 P3 deprotection, acylation 403Scheme 1 Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4 P3 deprotection thendialkylation with alkyl dibromide 404 Scheme 1 Cbz-Gly-OHFmoc-L-Dab(Boc)-OH Scheme 4 P3 deprotection, condensation 405 Scheme 1Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4 P3 deprotection, condensation,reduction 406 Scheme 1 Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4 P3deprotection then dialkylation with alkyl dibromide 407 Scheme 1Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4 P3 deprotection then dialkylationwith alkyl dibromide 408 Scheme 1 Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4P3 deprotection then dialkylation with alkyl dibromide 409 Scheme 1Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4 P3 deprotection then dialkylationwith alkyl dibromide 410 Scheme 1 Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4P3 deprotection then dialkylation with alkyl dibromide 411 Scheme 1Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4 P3 deprotection then dialkylationwith alkyl dibromide 412 Scheme 1 Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 3P3 deprotection then dialkylation with alkyl dibromide 413 Scheme 1Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 5 P3 deprotection then dialkylationwith alkyl dibromide 414 Scheme 1 Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 5P3 deprotection then dialkylation with alkyl dibromide 415 Scheme 1Cbz-Gly-OH Fmoc-L-Dap(Boc)-OH Scheme 5 P3 deprotection then dialkylationwith alkyl dibromide 416 Scheme 1 Cbz-Gly-OH Fmoc-L-Dap(Boc)-OH Scheme 5P3 deprotection then dialkylation with alkyl dibromide 417 Scheme 1Cbz-Gly-OH Fmoc-L-Orn(Boc)-OH Scheme 5 P3 deprotection then dialkylationwith alkyl dibromide 418 Scheme 1 Cbz-Gly-OH Fmoc-L-Orn(Boc)-OH Scheme 5P3 deprotection then dialkylation with alkyl dibromide 419 Scheme 1Boc-Aib Fmoc-L-Dab(Boc)-OH Scheme 4 P3 deprotection 420 Scheme 1 Boc-AibFmoc-L-Dab(Boc)-OH Scheme 4 P3 deprotection then dialkylation with alkyldibromide 421 Scheme 1 2-naphthoic-Gly- Fmoc-L-Dab(Boc)-OH Scheme 3 P3deprotection OH 422 Scheme 1 2-naphthoic-Gly- Fmoc-L-Dab(Boc)-OH Scheme3 P3 deprotection OH 423 Scheme 1 2-naphthoic-Gly- Fmoc-L-Dab(Boc)-OHScheme 3 P3 deprotection OH then dialkylation with alkyl dibromide 424Scheme 1 2-naphthoic-Gly- Fmoc-L-Dab(Boc)-OH Scheme 3 P3 deprotection OHthen dialkylation with alkyl dibromide 425 Scheme 1 Cbz-Gly-OHFmoc-L-Asp[N(Me)OMe]-OH Scheme 4 P3 conversion to aldehyde thenreductive amination 426 Scheme 1 Cbz-Gly-OH Fmoc-L-Asp[N(Me)OMe]-OHScheme 4 P3 conversion to aldehyde then reductive amination 427 Scheme 1Cbz-Gly-OH Fmoc-L-Asp[N(Me)OMe]-OH Scheme 4 P3 conversion to aldehydethen reductive amination 428 Scheme 1 Cbz-Gly-OH Fmoc-L-Dab(Boc)-OHScheme 4 P3 conversion to aldehyde then reductive amination 429 Scheme 1Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4 P3 conversion to aldehyde thenreductive amination 430 Scheme 1 Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4P3 conversion to aldehyde then reductive amination 431 Scheme 1Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4 P3 conversion to aldehyde thenreductive amination 432 Scheme 1 2-naphthoic-Gly- Fmoc-L-Dab(Boc)-OHScheme 3 P3 deprotection OH then dialkylation with alkyl dibromide 433Scheme 1 2-naphthoic-Gly- Fmoc-L-Dab(Boc)-OH Scheme 3 P3 deprotection OHthen dialkylation with alkyl dibromide 434 Scheme 1 Cbz-Gly-OHFmoc-L-Dab(Boc)-OH Scheme 4 P3 deprotection then dialkylation with alkyldibromide 435 Scheme 1 Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4 none 436Scheme 1 Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4 P3 deprotection thendialkylation with alkyl dibromide 437 Scheme 1 Cbz-Gly-OHFmoc-L-Dab(Boc)-OH Scheme 4 none 438 Scheme 1 Alloc-Gly-OHFmoc-L-Dab(Boc)-OH Scheme 4 P3 deprotection, reductive alkylation 439Scheme 1 Alloc-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4 P3 deprotection,reductive alkylation 440 Scheme 1 Alloc-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme4 P3 deprotection, reductive alkylation 441 Scheme 1 Alloc-Gly-OHFmoc-L-Dab(Boc)-OH Scheme 3 P3 deprotection 442 Scheme 1 Cbz-Gly-OHFmoc-L-Asp[N(Me)OMe]-OH Scheme 4 P3 conversion to aldehyde thenreductive amination 443 Scheme 1 Cbz-Gly-OH Fmoc-L-Asp[N(Me)OMe]-OHScheme 4 P3 conversion to aldehyde then reductive amination 444 Scheme 1Cbz-Gly-OH Fmoc-L-Asp[N(Me)OMe]-OH Scheme 4 P3 conversion to aldehydethen reductive amination 445 Scheme 1 Cbz-Gly-OH Fmoc-L-Asp[N(Me)OMe]-OHScheme 4 P3 conversion to aldehyde then reductive amination 446 Scheme 1Cbz-Gly-OH Fmoc-L-Asp[N(Me)OMe]-OH Scheme 4 P3 conversion to aldehydethen reductive amination 447 Scheme1 Cbz-Gly-OH N-Fmoc-1(1-Boc- Scheme 4P3 deprotection piperidin-4yl)-D,L-Gly-OH 448 Scheme1 Cbz-Gly-OHN-Fmoc-1(1-Boc- Scheme 4 P3 deprotection, piperidin-4yl)-D,L-Gly-OHreductive alkylation 449 Scheme 1 Cbz-Gly-OH Fmoc-L-Asp[N(Me)OMe]-OHScheme 4 P3 conversion to aldehyde then reductive amination 450 Scheme 1Cbz-Gly-OH Fmoc-L-Asp[N(Me)OMe]-OH Scheme 4 P3 conversion to aldehydethen reductive amination 451 Scheme 1 Cbz-Gly-OH Fmoc-L-Asp[N(Me)OMe]-OHScheme 4 P3 conversion to aldehyde then reductive amination 452 Scheme 1Cbz-Gly-OH Fmoc-L-Asp[N(Me)OMe]-OH Scheme 4 P3 conversion to aldehydethen reductive amination 453 Scheme 1 Cbz-Gly-OH Fmoc-L-Asp[N(Me)OMe]-OHScheme 4 P3 conversion to aldehyde then reductive amination 454 Scheme 1Cbz-Gly-OH Fmoc-L-Asp[N(Me)OMe]-OH Scheme 4 P3 conversion to aldehydethen reductive amination 455 Scheme 1 Cbz-Gly-OH N-Fmoc-1-(1-Boc- Scheme4 P3 deprotection, piperidin-4-yl)-D,L-Gly-OH reductive alkylation 456Scheme 1 Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 5 P3 deprotection,alkylation 457 Scheme 1 Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 5 P3deprotection, alkylation 458 Scheme 1 Cbz-Gly-OH Fmoc-L-Dab(Boc)-OHScheme 5 P3 deprotection, alkylation 459 Scheme 1 Boc-Gly-OHCbz-DL-γ-nitro-Leu-OH Scheme 4 P3 reduction to amine 460 Scheme 1Boc-Gly-OH Cbz-DL-γ-nitro-Leu-OH Scheme 4 P3 reduction to amine 461Scheme 1 Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4 P3 deprotection 462Scheme 1 Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4 P3 deprotection 463Scheme 1 Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4 P3 deprotection,dialkylation with alkyl dibromide 464 Scheme 1 Cbz-Gly-OHFmoc-L-Dab(Boc)-OH Scheme 4 P3 deprotection 465 Scheme 1 Cbz-Gly-OHFmoc-L-Dab(Boc)-OH Scheme 4 P3 deprotection then reductive alkylation466 Scheme 1 Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4 P3 deprotection 467Scheme 1 Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4 P3 deprotection thendialkylation 468 Scheme 1 Boc-Gly-OH Cbz-DL-γ-nitro-Leu-OH Scheme 4 P3reduction to amine then dialkylation with alkyl dibromide 469 Scheme 1Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4 P3 deprotection 470 Scheme 1Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4 P3 deprotection 471 Scheme 1Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4 P3 deprotection, dialkylationwith alkyl dibromide 472 Scheme 1 Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4P3 deprotection, dialkylation with alkyl dibromide 473 Scheme 1Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 5 P3 deprotection, alkylation 474Scheme 1 Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 5 P3 deprotection,alkylation 475 Scheme 1 Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4 P3deprotection 476 Scheme 1 Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4 P3deprotection, dialkylation with alkyl dibromide 477 Scheme 1 Cbz-Gly-OHFmoc-L-Dab(Boc)-OH Scheme 4 P3 deprotection 478 Scheme 1 Cbz-Gly-OHFmoc-L-Dab(Boc)-OH Scheme 4 P3 deprotection, dialkylation with alkyldibromide 479 Scheme 1 Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4 P3deprotection, dialkylation with alkyl dibromide 480 Scheme 2 Boc-Gly-OHBoc-L-Arg(Cbz)₂-OH Scheme 4 P3 deprotection 481 Scheme 2 Boc-Gly-OHBoc-L-Arg(Cbz)₂-OH Scheme 4 P3 deprotection 482 Scheme 2 Boc-Gly-OHBoc-L-Arg(Cbz)₂-OH Scheme 4 P3 deprotection 483 Scheme 1 Boc-Gly-OHCbz-L-Asp[N(Me)OMe] Scheme 4 P3 conversion to aldehyde then reductiveamination 484 Scheme 1 Boc-Gly-OH Cbz-L-Asp[N(Me)OMe] Scheme 4 P3conversion to aldehyde then reductive amination 485 Scheme 1 Cbz-Gly-OHFmoc-L-Dab(Boc)-OH Scheme 5; P3 deprotection reductive then dialkylationalkylation for with alkyl dibromide R1X 486 Scheme 1 Cbz-Gly-OHFmoc-L-Dab(Boc)-OH Scheme 4 P3 deprotection then dialkylation with alkyldibromide 487 Scheme 1 Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4 P3deprotection 488 Scheme 1 Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4 P3deprotection then dialkylation with alkyl dibromide 489 Scheme 1Cbz-Gly-OH Fmoc-L-Dab(Boc) Scheme 4 P3 deprotection, diacylation withanhydride 490 Scheme 1 Cbz-Gly-OH Boc-L-citrulline-OH Scheme 4 none 491Scheme 1 Cbz-Gly-OH Fmoc-L-Dab(Boc) Scheme 4 P3 deprotection, reductivealkylation 492 Scheme 1 Cbz-Gly-OH Fmoc-L-Dab(Boc) Scheme 4 P3deprotection, diacylation with anhydride 493 Scheme 1 Cbz-Gly-OHFmoc-L-Dab(Boc) Scheme 4 P3 deprotection then dialkylation with alkyldibromide 494 Scheme 1 Cbz-Gly-OH Fmoc-L-Dab(Boc) Scheme 4 P3deprotection, then acylation with isocyanate 495 Scheme 1 Cbz-Gly-OHFmoc-L-Dab(Boc)-OH Scheme 5 P3 deprotection then dialkylation with alkyldibromide 496 Scheme 1 Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 5 P3deprotection then dialkylation with alkyl dibromide 497 Scheme 1Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 5 P3 deprotection then dialkylationwith alkyl dibromide 498 Scheme 1 Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4P3 deprotection then reductive alkylation then acetylation 499 Scheme 1Cbz-Gly-OH Fmoc-L-Dap(Boc)-OH Scheme 4 P3 deprotection then reductivealkylation 500 Scheme 1 Cbz-Gly-OH Fmoc-L-Dap(Boc)-OH Scheme 4 P3deprotection then guanylation 510 Scheme 1 Cbz-Gly-OH Fmoc-L-Dab(Boc)-OHScheme 5 P3 deprotection, guanidinylation, deprotection 502 Scheme 1Alloc-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4 P3 deprotection 503 Scheme 1Alloc-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4 P3 deprotection thendialkylation with alkyl dibromide 504 Scheme 1 Alloc-Gly-OHFmoc-L-Dab(Boc)-OH Scheme 4 P3 deprotection then sulfonylation 505Scheme 1 Alloc-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4 P3 deprotection thensulfonylation 506 Scheme 1 Alloc-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4 P3deprotection, acylation, deprotection 507 Scheme 1 Alloc-Gly-OHFmoc-L-Dab(Boc)-OH Scheme 4 P3 deprotection 508 Scheme 1 Alloc-Gly-OHFmoc-L-Dab(Boc)-OH Scheme 4 P3 deprotection then dialkylation with alkyldibromide 509 Scheme 1 N-(6-Cl-2- Fmoc-L-Dab(Boc)-OH Scheme 3 P3deprotection napthoic)-Gly-OH 510 Scheme 1 N-(6-Cl-2- Fmoc-L-Dab(Boc)-OHScheme 3 P3 deprotection napthoic)-Gly-OH then dialkylation with alkyldibromide 511 Scheme 1 N-(6-Cl-2- Fmoc-L-Dab(Boc)-OH Scheme 3 P3deprotection napthoic)-Gly-OH then dialkylation with alkyl dibromide 512Scheme 1 Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4 P3 deprotection 513Scheme 1 Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4 P3 deprotection thendialkylation with alkyl dibromide 514 Scheme 1 Cbz-Gly-OHFmoc-L-Dab(Boc)-OH Scheme 4 P3 deprotection then dialkylation with alkyldibromide 515 Scheme 1 Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4 P3deprotection then dialkylation with alkyl dibromide 516 Scheme 1Alloc-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4 P3 deprotection thendialkylation with alkyl dibromide 517 Scheme 1 Alloc-Gly-OHFmoc-L-Dab(Boc)-OH Scheme 4 P3 deprotection then dialkylation with alkyldibromide 518 Scheme 1 Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 5, P3deprotection use then dialkylation isocyanate with alkyl dibromide forR1X 519 Scheme 1 Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 5; P3 deprotectionreductive then dialkylation alkylation with alkyl dibromide thenacetylation for R1X and R2 520 Scheme 1 Cbz-Gly-OH Fmoc-L-Dab(Boc)-OHScheme 4 P3 deprotection 521 Scheme 1 Cbz-Gly-OH Fmoc-L-Dab(Boc)-OHScheme 4 P3 deprotection then dialkylation with alkyl dibromide 522Scheme 1 Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4 P3 deprotection thendialkylation with alkyl dibromide 523 Scheme 1 Cbz-Gly-OHFmoc-L-Dab(Boc)-OH Scheme 4 P3 deprotection then sulfonylation 524Scheme 1 Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4 P3 deprotection thenacylation with chloroformate 525 Scheme 1 Cbz-Gly-OH Fmoc-DL-2-(1-Boc-4-Scheme 4 P3 deprotection piperidyl)-Gly-OH then reductive alkylationwith ketone 526 Scheme 1 Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4 P3deprotection then dialkylation with alkyl dibromide 527 Scheme 1Alloc-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 5 P3 deprotection thendialkylation with alkyl dibromide 528 Scheme 1 Alloc-Gly-OHFmoc-L-Dab(Boc)-OH Scheme 5 P3 deprotection then dialkylation with alkyldibromide 529 Scheme 1 Alloc-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 5 P3deprotection then dialkylation with alkyl dibromide 530 Scheme 1Cbz-[¹⁵N,1,2- Fmoc-L-Dab(Boc)-OH Scheme 4 P3 deprotection 13C₂]Gly-OHthen reductive alkylation then acetylation 531 Scheme 1 Alloc-Gly-OHFmoc-L-Dab(Boc)-OH Scheme 5 P3 deprotection then dialkylation with alkyldibromide 532 Scheme 1 Alloc-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 5 P3deprotection then dialkylation with alkyl dibromide 533 Scheme 1Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 5 P3 deprotection then dialkylationwith alkyl dibromide 534 Scheme 1 Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 5P3 deprotection then dialkylation with alkyl dibromide 535 Scheme 1Alloc-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 5 P3 deprotection thendialkylation with alkyl dibromide 536 Scheme 1 Alloc-Gly-OHFmoc-L-Dab(Boc)-OH Scheme 5 P3 deprotection then dialkylation with alkyldibromide 537 Scheme 1 Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 5 P3deprotection then dialkylation with alkyl dibromide 538 Scheme 1Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 5 P3 deprotection then dialkylationwith alkyl dibromide 539 Scheme 1 Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 5P3 deprotection then dialkylation with alkyl dibromide 540 Scheme 1Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4 P3 deprotection with D₂O thenreductive exchange alkylation then during acetylation Fmoc deprotectionand NaBD₃CN reduction 541 Scheme 1 Cbz-Gly-OH Fmoc-D-Dab(Boc)-OH Scheme4 P3 deprotection then dialkylation with alkyl dibromide 542 Scheme 2Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4 P3 deprotection then dialkylationwith alkyl dibromide 543 Scheme 2 Cbz-Gly-OH Fmoc-D-Dab(Boc)-OH Scheme 4P3 deprotection then dialkylation with alkyl dibromide 544 Scheme 2Cbz-Gly-OH Fmoc-L-Dab(Boc)-OH Scheme 4 P3 deprotection then dialkylationwith alkyl dibromide 545 Scheme 2 Cbz-Gly-OH Fmoc-D-Dab(Boc)-OH Scheme 4P3 deprotection then dialkylation with alkyl dibromide 546 Scheme 1Cbz-Gly-OH Fmoc-D-Dab(Boc)-OH Scheme 4 P3 deprotection then dialkylationwith alkyl dibromide

Example 102 Human MC5R Radioligand Binding Assay

Assessments of compound binding to human MC5R (hMC5R)) by displacementof an ¹²⁵I-labeled NDP-MSH receptor ligand peptide were performedessentially as described in the data sheets produced by Perkin Elmer toaccompany their frozen hMC5R membranes (Perkin Elmer catalog numberRBXMC5M400UA).

[¹²⁵I] NDP-MSH: Radiolabeled in House and Purified by HPLC: Na¹²⁵I (0.5mCi, 17.4 Ci/mg) was added to 50 μL sodium phosphate (50 mM, pH7.4) inan eppendorf tube precoated with IODOGEN. After incubation for 10 minsthe phosphate buffer containing the iodine was added to NDP-MSH (10 ulat 1 mg/mL) in a separate eppendorf tube. This was incubated for afurther 10 mins. The iodinated NDP-MSH was purified by HPLC on a ZorbaxSB 300 column using solvent A: 0.05% TFA and solvent B: 90% acetonitrile0.045% TFA with a linear gradient, 0-67% B over 60 mins. The ¹²⁵INDP-MSH eluted at 52 min after the unlabeled starting material (48 min)and was counted and stored in the freezer. It was used within 48 hrs, asradioactive decay and ligand decomposition resulted in greatly reducedspecific binding observed after 72 hrs.Reagents:

Incubation buffer: 25 mM HEPES-KOH (pH 7.0), 1.5 mM CaCl₂, 1 mM MgSO₄,0.1M NaCl, 1 mM 1,10-phenanthroline, and 1 Complete™ protease inhibitortablet/100 mL (Roche, catalog number 1873580)

Perkin Elmer frozen hMC5 membranes: catalog number RBXMC5M400UA, 0.4mL/vial; 400 microassays/vial, 0.78 mg/mL protein concentration

Vials of frozen membranes were thawed rapidly immediately before use,diluted with binding buffer and vortexed. Resuspended membranes werekept on ice until they were added to the wells of the plate.

Binding Protocol for 400 Microassays Per Vial:

Assays were performed in 96 well polypropylene plates. Membranes (0.78μg, 40 μL of a 1:40 dilution in incubation buffer) were added to [¹²⁵I]NDP-MSH (0.84 nM; 2200 Ci/mmol) and test compounds in a total volume of140 μL. This was incubated for 1 hr at 37° C. Non-specific binding wasdetermined with 3 mM NDP-MSH. Plates were filtered using a Tomtec cellharvester with GF/A filters (Wallac) (presoaked in 0.6%polyethylenimine) and washed three times with 1.0 mL ice-cold washbuffer (the above incubation buffer without 1,10-phenanthroline andComplete™ protease inhibitor tablet). The filters were dried in a 37° C.oven, placed in a sample bag and 5 mL Betaplatescint (Wallac) was added.Prepared filters were counted in cassettes in a Microbeta Trilux(Wallac) for 1 min. Non-specific binding just under 5%. Data analysiswas performed using GraphPad Prism 4, employing competition binding witha single site model and a fixed Hill coefficient. The following equationwas used: Y=Bottom+(Top-Bottom)/ 1/10^(X-log EC₅₀), whereX=log(concentration) and Y=binding to fit the data.

Example 103 Identification of Preferred Diastereomer for Binding to MC5R

The four diastereomers of one set of substituents were tested forbinding in the hMC5R assay as in Examples 102, as listed in Table 3.

TABLE 3 Activity of Four Diastereomers human MC5R Cpd. stereochemistryIC₅₀ (nM) 102 (3R,5S) 3500 103 (3R,5R) 500 104 (3S,5R) 1500 105 (3S,5S)56

As can be seen the 3S, 5S isomer is almost ten times more active thanthe next most active isomer and significantly more active than the othertwo possible isomers. This unexpectedly high level of differentialactivity and hence specificity of the (S,S) diastereoisomer wasunexpected and is not predictable from a knowledge of the hMC5R or itspreviously known ligands.

Example 104 Activity of Selected Compounds: hMC5R Binding

Representative compounds of the present invention were tested forbinding in the hMC5R assay as in Example 102, with the results listed inTable 4. The compounds were tested as their trifluoroacetate orhydrochloride salts, or as their free bases.

TABLE 4 Properties of Compounds MC5R radioligand Cpd. MS (M + 1) t_(R)(min) IC₅₀ 14 556.2 5.74 xxx 25 595.3 6.22 xxx 31 539.3 5.92 xx 33 599.46.31 xxxx 37 473.4 5.59 xxx 38 541.3 5.78 xxx 39 541.3 5.67 xxx 49 499.35.77 xx 50 613.5 5.89 x 54 425.7 5.27 xx 60 629.4 6.27 x 62 629.3 6.22xx 63 535.3 5.76 xx 64 603.3 6.04 xxx 65 577.2 5.97 xxx 67 591.3 5.94xxxx 71 549.3 5.93 xx 79 606.4 6.033 x 81 743.4 5.489 xx 83 650.3 6.524xx 85 606.2 6.008 x 86 743.5 5.410 xx 87 650.4 6.424 x 105 577.3 5.79xxx 106 561.4 6.05 xx 107 524.3 5.63 xx 108 603.3 6.11 xxx 109 566.25.65 xx 110 591.2 5.82 xx 111 581.3 5.95 xxx 112 578.3 5.26 xxx 113579.3 5.52 xx 114 578.3 5.72 xx 115 527.3 5.41 xx 116 578.3 5.78 xx 117509.2 5.51 xx 118 523.3 5.56 x 119 523.2 5.51 x 120 512.3 5.100 x 121549.4 5.96 xx 122 509.2 5.56 xx 123 523.4 5.63 x 124 509.2 5.41 x 125523.3 5.68 x 126 549.3 5.79 xx 127 554.2 5.87 x 128 554.2 5.87 xx 129539.1 5.58 x 130 596.5 5.87 x 131 582.4 5.88 x 132 567.4 5.62 x 133567.4 5.62 x 134 582.4 5.88 xx 135 583.4 5.86 xx 136 595.4 5.31 xxx 137595.4 5.87 xx 138 527.2 5.33 xx 139 533.3 5.54 x 140 620.2 6.16 xxx 141620.2 6.21 xx 142 566.3 5.70 xxx 143 555.2 5.55 xx 144 555.2 5.74 xxx145 583.4 6.21 xx 146 587.2 4.90 x 147 547.4 5.78 xx 148 571.2 5.34 xx149 567.1 4.48 x 150 568.1 4.87 x 151 519.5 5.23 x 152 595.4 5.92 xxx153 553.5 5.58 xxx 154 595.4 5.95 xx 155 609.4 5.88 xx 156 607.5 5.96xxx 157 609.4 — x 158 607.4 5.88 xxx 159 621.3 6.22 xxx 160 585.6 6.00 x161 557.4 5.50 x 162 607.5 5.94 xx 163 607.2 5.69 xx 164 585.4 5.64 xx165 557.3 6.06 xxx 166 559.5 5.47 xxx 167 585.5 5.58 xx 168 569.5 5.17xx 169 583.6 5.70 xx 170 567.6 5.79 xxx 171 621.4 6.01 xx 172 571.5 5.65xxx 173 567.5 5.50 xx 174 567.5 5.37 xx 175 625.5 5.81 xxx 176 587.45.65 xxx 177 584.5 4.84 xx 178 593.4 5.60 xx 179 583.6 5.41 xx 180 655.25.97 xxxx 181 501.4 5.20 xx 182 570.2 5.64 x 183 570.2 5.66 xx 184 583.55.43 xxx 185 607.3 5.28 xxx 186 583.4 5.37 xxx 187 595.6 5.64 xxx 188587.4 5.78 xx 189 569.5 5.23 xx 190 567.7 5.92 xxx 191 621.4 6.19 xx 192569.6 5.23 xx 193 571.5 5.69 xxx 194 567.5 5.98 xxx 195 571.5 6.00 xx196 561.3 5.84 xx 197 575.4 5.98 xx 198 571.1 5.69 xxx 199 621.3 6.19xxx 200 591.2 6.02 xx 201 493.3 5.41 xx 202 545.2 5.91 xx 203 591.3 5.88xxx 204 591.3 5.90 xx 205 479.4 5.09 xx 206 609.4 6.13 xx 207 589.3 5.69xxx 208 605.3 5.85 xxx 209 631.4 6.09 xxxx 210 597.4 5.89 xxx 211 615.36.20 xxx 212 511.3 5.63 xx 213 545.4 5.92 xxx 214 637.6 6.15 xx 215605.5 5.94 xxx 216 553.3 5.88 xxx 217 592.4 4.99 x 218 525.3 5.79 xxx219 529.5 5.59 xxx 220 553.5 5.87 xxx 221 507.2 5.64 x 222 513.5 5.68 xx223 553.3 5.89 xxx 224 549.7 5.87 xx 225 617.4 6.21 xxx 226 523.3 5.49 x227 575.5 5.72 x 228 611.2 6.20 xxxx 229 591.4 6.03 xxx 230 547.5 5.70xxx 231 536.5 5.47 xx 232 561.7 6.11 xx 233 533.5 5.53 xx 234 585.5 6.23xxx 235 550.5 5.81 xxx 236 568.5 5.45 x 237 586.5 6.18 xxx 238 542.55.57 xx 239 568.4 5.91 xx 240 579.7 5.60 xx 241 565.5 5.42 x 242 506.45.73 xx 243 519.3 5.78 xx 244 637.5 5.84 x 245 624.3 6.28 xxx 246 603.26.14 xxx 247 589.4 6.04 xxx 248 543.3 6.30 xxx 249 487.2 5.13 x 250613.5 6.06 xxx 251 537.4 5.66 x 252 531.6 5.65 xx 253 551.5 5.47 xx 254543.5 5.77 x 255 543.5 5.66 xx 256 581.5 5.10 xx 257 591.4 5.94 xxx 258599.4 5.99 xxx 259 613.5 6.08 xxx 260 521.4 5.85 xx 261 589.3 5.81 xxx262 575.5 5.79 xxx 263 537.2 5.61 x 264 551.4 5.70 x 265 558.4 4.86 x266 579.6 5.73 xxx 267 581.4 5.84 xxx 268 621.2 6.07 xxx 269 598.6 5.27xx 270 626.7 5.64 x 271 507.3 6.35 xx 272 517.4 6.51 xxx 273 515.3 5.18xxx 274 511.4 5.81 xxx 275 575.3 6.71 xxx 276 585.4 6.83 xxxx 277 539.35.87 xx 278 499.5 5.62 xx 279 497.6 5.58 xx 280 531.4 5.89 xxx 281 607.36.29 xxxx 282 567.3 5.99 xxx 283 565.4 5.93 xxx 284 583.5 6.02 xxxx 285579.6 6.18 xxx 286 515.3 5.58 xx 287 620.5 5.44 xx 288 620.5 5.38 x 289531.5 5.22 xx 290 559.5 5.74 xx 291 607.4 6.06 xx 292 557.4 5.61 xx 293567.3 6.52 xx 294 635.5 7.34 xx 295 593.5 6.02 xxx 296 573.4 5.47 xx 297481.4 5.47 xx 298 521.5 6.10 xxx 299 641.4 7.38 xx 300 655.3 7.59 xx 301485.3 5.17 x 302 553.3 5.82 xx 303 535.3 5.72 xx 304 553.5 5.39 x 305621.2 6.06 xx 306 603.4 5.94 xx 307 572.3 4.91 x 308 519.2 5.93 xx 309511.2 5.94 xxx 310 540.3 5.61 xx 311 523.2 5.37 xx 312 498.4 5.49 xx 313481.5 5.27 x 314 514.3 5.52 x 315 514.2 5.42 x 316 505.4 5.27 x 317480.3 5.33 x 318 514.4 5.65 x 319 514.4 5.62 xx 320 514.3 5.63 x 321477.3 5.35 x 322 531.5 5.65 x 323 480.4 5.38 x 324 487.2 5.55 xx 325527.3 5.96 xx 326 587.2 6.33 xxx 327 567.3 6.12 xxx 328 577.2 6.31 xxxx329 443.2 5.43 xx 330 435.3 5.46 xx 331 503.1 5.58 xx 332 511.4 5.73 xxx333 493.7 5.71 xxx 334 427.3 5.04 x 335 423.4 5.28 x 336 427.3 5.13 x337 423.3 5.32 x 338 489.4 6.42 xx 339 589.4 5.92 xx 340 581.3 6.03 x341 480.4 5.33 x 342 555.4 5.81 xxx 343 612.6 5.49 x 344 620.5 — x 345595.4 6.12 xx 346 637.2 6.30 x 347 505.1 6.46 xx 348 485.2 6.26 xx 349491.2 5.69 xx 350 573.1 6.07 xx 351 565.2 6.88 xxx 352 491.2 5.69 xx 353483.4 5.77 xxx 354 559.1 6.12 xx 355 539.2 5.84 xx 356 473.3 5.29 xx 357473.2 5.21 x 358 549.4 6.03 xx 359 621.4 6.13 xxx 360 493.3 5.32 xx 361587.2 6.17 xxx 362 577.4 6.04 xxx 363 559.3 6.01 xxx 364 551.3 5.99 xxx365 551.4 6.04 xxxx 366 555.3 6.19 xxx 367 575.4 6.11 xxx 368 589.3 6.06xxx 369 443.6 5.36 xx 370 459.9 5.66 xx 371 503.2 5.74 xx 372 511.4 5.65xxx 373 527.3 5.95 xxx 374 573.2 6.07 xxx 375 483.3 5.97 xx 376 465.45.81 xx 377 475.3 5.98 xx 378 623.2 6.41 xxxx 379 607.4 6.17 xxxx 380585.4 6.12 xxx 381 573.2 6.12 xxx 382 563.4 5.95 xx 383 581.3 6.12 xx384 479.1 5.68 x 385 487.4 5.45 xx 386 551.5 6.42 xxx 387 525.3 6.31 xx388 487.3 5.69 x 389 473.4 5.51 xx 390 487.4 5.40 x 391 601.3 6.08 xxx392 533.3 5.82 x 393 622.3 6.90 x 394 555.4 6.00 xx 395 555.4 6.10 xxx396 607.5 6.60 xxx 397 539.4 6.32 xx 398 593.5 6.26 xxx 399 525.3 6.03xx 400 601.3 6.09 xxx 401 533.2 5.81 xx 402 627.4 7.20 x 403 601.3 6.10xxx 404 609.4 7.64 xx 405 613.4 6.31 xxx 406 575.3 6.26 xxxx 407 537.45.98 xxx 408 525.1 5.96 xxx 409 561.4 6.26 xxxx 410 559.1 6.11 xxx 411545.1 6.01 xxx 412 569.3 5.92 xx 413 645.3 6.28 xxxx 414 640.2 6.7 xxx415 561.4 6.88 xxx 416 545.1 6.68 xx 417 589.4 6.24 xxx 418 573.1 5.95xxx 419 559.1 5.90 xx 420 627.4 6.56 xx 421 493.2 5.68 x 422 493.2 5.71x 423 561.4 5.93 x 424 561.4 6.09 xx 425 581.3 6.93 xx 426 547.3 6.00xxx 427 561.2 5.92 xxx 428 567.2 6.94 xx 429 581.2 6.45 xxx 430 547.26.12 xxx 431 574.3 5.67 xxx 432 555.3 6.15 xxx 433 555.3 6.25 xxx 434607.2 6.20 xxx 435 539.2 5.90 x 436 607.3 6.11 xx 437 539.1 5.94 x 438577.1 6.37 xxxx 439 561.1 6.17 xxx 440 549.2 6.28 xxxx 441 507.2 6.00xxx 442 595.2 6.50 xxxx 443 560.3 5.64 xxx 444 575.2 6.62 xxx 445 575.26.27 xxxx 446 573.2 6.28 xxxx 447 547.2 5.96 xxx 448 617.2 6.52 xxx 449587.4 6.55 xxx 450 575.2 5.82 xxx 451 603.4 5.98 xxx 452 573.1 6.32 xxx453 573.1 6.18 xxxx 454 561.2 6.21 xxx 455 575.2 6.06 xxx 456 593.4 6.01xxx 457 549.2 5.87 xxx 458 563.3 6.05 xxx 459 457.2 5.64 x 460 457.25.78 x 461 525.2 6.05 xxx 462 525.3 6.13 xxx 463 535.2 6.33 xx 464 491.35.63 xx 465 533.2 5.94 xxx 466 533.1 6.44 xxx 467 603.3 6.44 xxx 468603.2 7.15 xxx 469 473.1 5.99 xx 470 473.2 6.09 xx 471 541.2 6.34 xxx472 541.1 6.43 xxx 473 633.4 5.66 xx 474 591.1 6.36 xxxx 475 455.2 5.16x 476 523.3 6.09 xx 477 471.1 5.53 xxxx 478 539.3 6.11 xxx 479 539.26.19 xxxx 480 519.3 5.72 xx 481 496.3 4.91 xxx 482 494.4 4.65 xx 483595.3 6.30 xxx 484 595.3 6.39 xx 485 545.2 5.91 xxx 486 523.0 5.88 xx487 471.1 5.79 xx 488 539.3 6.14 xxx 489 573.1 6.50 x 490 564.5 6.60 xx491 587.2 6.61 xx 492 601.3 7.03 x 493 589.3 6.59 xxx 494 592.3 7.08 xx495 567.3 6.34 xxx 496 574.2 6.14 xxx 497 601.3 6.69 xxx 498 591.3 7.24xx 499 535.3 6.94 xxx 500 535.3 6.37 xxx 510 573.1 6.13 xx 502 519.25.98 xx 503 587.1 6.34 xx 504 597.1 6.61 x 505 673.0 7.50 x 506 618.4 —x 507 533.1 6.20 xxx 508 603.1 6.57 xxx 509 513.3 6.00 xxx 510 581.26.22 xxx 511 581.0 6.33 xxxx 512 473.3 6.03 xx 513 541.1 6.36 xxx 514625.4 6.57 xxx 515 577.2 6.30 xxx 516 603.1 6.45 xxx 517 589.1 6.23 xxx518 554.3 6.02 xx 519 587.1 6.50 x 520 457.0 5.73 x 521 525.2 6.20 xxx522 637.0 6.75 xxx 523 613.3 7.03 xxx 524 607.2 — xx 525 589.5 6.19 xxx526 574.8 6.27 xxxx 527 618.9 6.74 xxx 528 587.7 6.19 xxxx 529 596.96.20 xxx 530 578.0 6.38 xxxx 531 597.0 6.42 xxx 532 626.9 6.70 xxxx 533591.9 6.61 xxxx 534 559.0 6.03 xxxx 535 612.8 7.04 xx 536 644.9 6.79 xxx537 570.9 6.04 xxx 538 570.8 6.21 xxx 539 618.8 6.61 xxxx 540 579.9 6.39xxxx x = <10 μM; xx = <1 μM, xxx = <100 nM, xxxx = <10 nM

Example 105 MC5R Radioligand Binding Assay Using MC5 Receptors fromOther Species

Radioligand binding and cAMP assays were also conducted using membranesand cells expressing MC5R cloned from other species (mouse MC5Rmembranes were obtained from Euroscreen; canine, rhesus monkey, cynomonkey and guinea pig MC5 receptors were cloned and expressed from cDNAlibraries and transiently transfected as described in Examples 107 and109. Plasma membranes from the cells were tested in the radioligandassay as in Example 102.

Example 106 Activity of Selected Compounds: Other Species MC5R

Representative compounds of the present invention were tested forbinding to MC5R from other species, as described in Example 105, theresults are listed in Table 5.

TABLE 5 Binding of Selected Compounds to MC5R from Different Speciesrhesus human human canine monkey MC5R MC5R MC5R rhesus MC5R (mem- (wholemouse (whole monkey (whole brane) cells) MC5R cells) MC5R cells) IC₅₀IC₅₀ (membrane) IC₅₀ (membranes) IC₅₀ Cpd. (nM) (nM) IC₅₀ (nM) (nM) IC₅₀(nM) (nM) 105 57 219 4000 6400 6027 3000 64 30 127 — 13000 7307 >5000

These results show the selectivity of the compounds of the invention forhuman MC5R in comparison to MC5R in other species. Whilst there isactivity in other species it is significantly reduced in comparison tohuman MC5R, which would not be expected given the high receptor homologybetween species.

Example 107 Human MC1R, MC3R and MC4R Radioligand Binding Assay

Radioligand binding assays were carried out using commercial or in-houseprepared hMC1R, hMC3R and hMC4R membranes and [¹²⁵I] NDP-MSH, as per thehMC5R procedure in Example 102.

In-house plasma membranes were prepared from transfected mammalian cells(prepared as in Example 109, using plasmid DNA containing the humanMC1R, MC3R or MC4R gene or other gene of interest in a plasmid vectorwith a mammalian origin of replication):

Adherent cells were washed with warm Hanks buffered saline solution(HBSS). 1 mL of cold HBSS was added to each flask and the cells werescraped off with a rubber policeman. The scraped cells were added to a50 mL tube on ice. The plates were then rinsed twice with 5 mL cold HBSSand this was also added to the tube. The cells were centrifuged at1000×g for 5 mins in a bench top centrifuge and the supernatant wasdecanted. The remaining cell pellet was resuspended in 0.25 M sucrose.The cell suspension was centrifuged again as previously and the pelletresuspended in 5 mL of 0.25 M sucrose containing protease inhibitors.The cells were homogenised by a 10 second pulse with an Ika disperserfollowed by 30 seconds on ice. The homogenisation and ice incubation wasrepeated three times. The mixture was then centrifuged at 1260×g for 5mins. The supernatant was decanted into another centrifuge tube, towhich a buffer containing 50 mM Tris, pH 7.4, 12.5 mM MgCl₂, 5 mM EGTAand protease inhibitors was added to make the volume up to 30 mL. Thiswas centrifuged at 30,000×g for 90 mins at 4° C. The resulting pelletwas resuspended in 1 mL of the buffer above also containing 10%glycerol. Membranes were aliquoted into cryovials which were snap-frozenin a dry-ice/ethanol bath before being stored at −80° C. until requiredfor use.

Example 108 Melanocortin Receptor Subtype Selectivity of SelectedCompounds: hMCR Binding

Representative compounds of the present invention were tested forbinding in the hMC1R, hMC3R, hMC4R and hMC5R assays, as in Examples 103and 108, as listed in Table 6.

TABLE 6 hMCR Binding Selectivity of Selected Compounds human MC5R humanMC1R human MC3R human MC4R Cpd. IC₅₀ (nM) IC₅₀ (nM) IC₅₀ (nM) IC₅₀ (nM)105 57 6660 1750 3280 64 31 9220 2240 3490 33 9 2850 1500 6060 331 15020000 1830 20000

These results demonstrate the selectivity of the compounds of theinvention for human MC5R in comparison to other receptor subtypes of thehuman melanocortin receptor family.

Example 109 Inhibition or Stimulation of cAMP Signal in Cells Expressinghuman MC5R

Transient Transfection of Mammalian Cell Lines:

The mammalian cell line, human embryonic kidney cells (HEK 293), weremaintained in Dulbeccos Modified Eagle's medium (DMEM) with 5% fetalbovine serum (BSA), L-glutamine, high glucose andantibiotics/antimycotics. On the day prior to transfection, cells werepassaged using trypsin/EDTA and seeded into 75 cm² flasks so that theywould be approximately 90% confluent the next day. The next day, thecell media was replaced with fresh antibiotic/antimycotic-containingDMEM. Approximately 100 μl of the transfection lipid Turbofectin 8.0(Origene Technologies, MD, USA), was diluted in 1.0 mL of serum andantibiotic/antimycotic-free OptiMEM in a sterile 15 mL tube andincubated for 5 mins at room temperature. Following incubation,approximately 10-20 μg of plasmid DNA expressing the gene of interest(for example: pCMV6-XL4:Homo sapiens melanocortin 5 receptor (OrigeneTechnologies, MD, USA)) was diluted into the transfection mix andincubated for a further 30 mins at room temperature. The DNA/lipidsolution was then added drop-wise to the media covering the cells whilerocking the flask gently. 24 hrs post-transfection, the cells werepassaged and seeded directly into two, 75 cm² flasks and left torecover. 48 hrs post transfection, cells were harvested for use inassays with cell dissociation solution.

Cyclic-Adenosine Monophosphate [cAMP] Stimulation Assay:

HEK 293 cells transiently expressing the human MC5R were suspended instimulation buffer (Hanks buffered saline solution (HBSS), 0.1% BSA,protease inhibitors and 0.5 mM 3-Isobutyl-1-methylxanthine) at 4×10⁶cells/mL. 5 μl of cells, plus the compounds/peptides as described below,were added to wells of a 384-well plate as soon as possible afterresuspension.

To detect antagonist activity, test compounds at varying concentrationswere diluted in stimulation buffer at four times concentrate and 2.5 μlwas added to wells containing cells. 2.5 μl of a four times requiredconcentration of NDP-MSH or alpha-MSH was added to all wells containingcompounds. Negative control wells contained two times concentratedNDP-MSH or alpha-MSH alone without compound.

To detect agonist activity, test compounds at varying concentrationswere diluted in stimulation buffer at two times concentrate and 5 μl wasadded to wells containing cells. Positive control wells containedNDP-MSH or alpha-MSH alone (no compound) at two times concentrate.

Basal level (of cAMP) control wells contained stimulation buffer only(no agonist or compounds). Known concentrations of cAMP (standards) instimulation buffer were included on the plate, but no cells were addedto these wells. The plate was then incubated for 30 mins at 37° C. withgentle shaking. After incubation, 10 μl of lysis buffer (10% Tween 20, 1M HEPES, 0.1% BSA, protease inhibitors, ddH₂O) was added to all wells tobe measured. Detection of cAMP was then achieved using the AlphascreencAMP kit (Perkin Elmer, USA), briefly described as follows. A dilutionof 10 μl acceptor beads/mL of lysis buffer was prepared in low lightconditions. 5 μl of diluted acceptor beads were added to each well to bemeasured, then the plate was incubated for 30 mins at room temperature,in the dark, with gentle shaking. In low light conditions, donor beadswere diluted at 10 μl/mL of lysis buffer, to which 0.75 μl biotinylatedcAMP/mL of lysis buffer was added. This mixture was allowed to incubatefor 30 mins at room temperature (in the dark) before proceeding with theassay. Following incubation, 5 μl/mL of biotinylated cAMP/Donor bead mixwere added per well in low light conditions and the plate was incubatedin the dark, at room temperature, for a further hr. Plates were read onan Envision plate reader (Perkin Elmer) after 1 hr and ˜16 hrsincubation. cAMP concentration in the cells was determined by the use ofa ‘standard curve’ generated from the output of known cAMPconcentrations as described below.

Each assay plate contained a “standard curve” of known concentrations ofcAMP, in 10 fold dilutions. This is an essential part of the assay asthere is high inter-plate variability. The plates were read on anEnvision multilabel plate reader fitted with Alphascreen technology andthe raw data was imported into GraphPad Prism 4 software (GraphPad, USA)for analysis. A curve was fitted to the known concentrations usingnon-linear regression, specifically using a sigmoidal dose-responseequation (Y=Bottom+(Bottom+(Top-Bottom)/1+10^(log EC50-X)), where theequation shows the response as a function of the logarithm ofconcentration. X is the logarithm of peptide/compound concentration andY is the response. Also considered in this equation are bottom plateau,top plateau of the curve and EC₅₀ (effective concentration, 50%)

Example 110 Activity of Selected Compounds: hMC5R

Representative compounds of the present invention were tested foragonism or antagonism of the hMC5R, as in Example 109, the results arelisted in Table 7.

TABLE 7 Agonism and Antagonism of hMC5 by Selected Compounds human MC5REC₅₀ human MC5R IC₅₀ (cAMP, agonism) (cAMP, antagonism of 10⁻⁶ M Cpd.(nM) alpha-MSH) (nM) 105 >10000 400 64 >10000 70 33 >10000 190331 >10000 94

REFERENCES

-   Andersen, G. N.; Hägglund, M.; Nagaeva, O.; Frangsmyr, L.;    Petrovska, R.; Mincheva-Nilsson, L.; Wikberg, J. E. S. Scand. J.    Immunol. 2005, 61, 279-284 “Quantitative measurement of the levels    of melanocortin receptor subtype 1, 2, 3 and 5 and    pro-opio-melanocortin peptide gene expression in subsets of human    peripheral blood leukocytes”-   Barrett, P.; MacDonald, A.; Helliwell, R.; Davidson, G.;    Morgan, P. J. Molec. Endocrin. 1994, 12, 203-213 “Cloning and    expression of a new member of the melanocyte-stimulating hormone    receptor family”-   Bataille, V.; Snieder, H.; MacGregor, A. J.; Sasieni, P.;    Spector, T. D. J. Invest. Dermatol. 2002, 119, 1317-1322 “The    Influence of Genetics and Environmental Factors in the Pathogenesis    of Acne: A Twin Study of Acne in Women”-   Bhardwaj, S. S.; Rohrer, T. E.; Arndt, K. A. Semin. Cutan. Med.    Surg. 2005, 24, 107-112 “Lasers and light therapy for acne vulgaris”-   Bohm, M.; Luger, T. A.; Tobin, D. J.; Garcia-Borron, J. C. J.    Invest. Dermatol. 2006, 126, 1966-1975 “Melanocortin Receptor    Ligands: New Horizons for Skin Biology and Clinical Dermatology”-   Buggy, J. J. Biochem J. 1998, 331, 211-216 “Binding of    a-melanocyte-stimulating hormone to its G-protein-coupled receptor    on B-lymphocytes activates the Jak/STAT pathway”-   Burke, B. M.; Cunliffe, W. J.; Br. J. Dermatol. 1984, 112 124-126    “Oral spironolactone therapy for female patients with acne,    hirsutism or androgenic alopecia”-   Caldwell, H. K.; Lepri, J. J. Chem. Senses 2002, 27, 91-94    “Disruption of the fifth melanocortin receptor alters the urinary    excretion of aggression-modifying pheromones in male house mice”-   Cerdá-Reverter, J. M.; Ling, M. K.; Schiöth, H. B.; Peter, R. E. J.    Neurochem. 2003, 1354-1367 “Molecular cloning, characterization and    brain mapping of the melanocortin 5 receptor in goldfish”-   Chen, W.; Kelly, M. A.; Opitz-Araya, X.; Thomas, R. E.; Low, M. J.;    Cone, R. D. Cell, 1997, 91, 789-798 “Exocrine gland dysfunction in    MC5-R-deficient mice: evidence for coordinated regulation of    exocrine gland function by melanocortin peptides”-   Chhajlani, V.; Muceniece, R.; Wikberg, J. E. S. BBRC 1993, 195,    866-873 “Molecular Cloning of a Novel Human Melanocortin Receptor”-   Clarke, S. B.; Nelson, A. M.; George, R. E.; Thiboutot, D. M.    Dermatol. Clin. 2007, 25, 137-146 “Pharmacologic Modulation of    Sebaceous Gland Activity: Mechanisms and Clinical Applications”.-   Cordain, L. Sem. Cut. Med Surg. 2005, 24, 84-91 “Implications for    the Role of Diet in Acne”-   Cotterill, J. A.; Cunliffe, W. J.; Williamson, B. Brit. J. Dermatol.    1971, 85, 93-94 “Severity of Acne and Sebum Excretion Rate”-   Danby, F. W. J. Am. Acad. Dermatol. 2005, 52, 1071-1072 “Why we have    sebaceous glands”-   Eisinger, M.; Fitzpatrick, L. J.; Lee, D. H.; Pan, K.;    Plata-Salaman, C.; Reitz, A. B.; Smith-Swintosky, V. L.; Zhao, B.    WO03/040117 15 May 2003a “Novel 1,2,4-thiadiazole derivatives as    melanocortin receptor modulators”-   Eisinger, M.; Fitzpatrick, L. J.; Lee, D. H.; Pan, K.;    Plata-Salaman, C.; Reitz, A. B.; Smith-Swintosky, V. L.; Zhao, B.    WO03040118A1 15 May 2003b “Novel 1,2,4-thiadiazolium derivatives as    melanocortin receptor modulators”-   Eisinger, M.; Fitzpatrick, L. J.; Lee, D. H.; Pan, K.;    Plata-Salaman, C.; Reitz, A. B.; Smith-Swintosky, V. L.; Zhao, B.    US2003/0162819A1 Aug. 28, 2003c “Novel 1,2,4-thiadiazolium    derivatives as melanocortin receptor modulators”-   Eisinger, M.; Fitzpatrick, L. J.; Lee, D. H.; Pan, K.;    Plata-Salaman, C.; Reitz, A. B.; Smith-Swintosky, V. L.; Zhao, B.    US2003/0176425A1 Sep. 18, 2003d “Novel 1,2,4-thiadiazole derivatives    as melanocortin receptor modulators”-   Eisinger, M.; Fitzpatrick, L. J.; Lee, D. H.; Pan, K.;    Plata-Salaman, C.; Reitz, A. B.; Smith-Swintosky, V. L.; Zhao, B.    US2006/0030604A1 Feb. 9, 2006a “Novel 1,2,4-thiadiazolium    derivatives as melanocortin receptor modulators”-   Eisinger, M.; Fitzpatrick, L. J.; Lee, D. H.; Pan, K.;    Plata-Salaman, C.; Reitz, A. B.; Smith-Swintosky, V. L.; Zhao, B.    US2006/0128772A1 Jun. 15, 2006b “Novel 1,2,4-thiadiazole derivatives    as melanocortin receptor modulators”-   Fathi, Z.; Iben, L. G.; Parker, E. M. Neurochemical Res. 1995, 20,    107-113 “Cloning, Expression, and Tissue Distribution of a Fifth    Melanocortin Receptor Subtype”-   Follador, I.; Campelo, L. Expert Rev. Dermatol. 2006, 1 181-184    “Impact of acne on quality of life”-   Fong, T. M.; Van der Ploeg, L. H. T.; Huang, R.-R. C. U.S. Pat. No.    6,645,738B1 Nov. 11, 2003 “DNA molecules encoding the melanocortin 5    receptor protein from rhesus monkey”-   Gantz, I.; Shimoto, Y.; Konda, Y.; Miwa, H.; Dickinson, C. J.;    Yamada, T. BBRC 1994, 200, 1214-1220 “Molecular cloning, expression    and characterization of a fifth melanocortin receptor”-   Goldstein, J. A.; Socha-Szott, A.; Thomsen, R. J.; Pochi, P. E.;    Shalita, A. R.; Strauss, J. S. Am. J. Dermatol. 1982, 6, 760-765    “Comparative effect of isotretinoin and etretinate on acne and    sebaceous gland secretion”-   Goodfellow, A.; Alaghband-Zadeh, J.; Carter, G.; Cream, J. J.;    Holland, S.; Scully, J.; Wise, P. Brit. J. Dermatol. 1984, 111,    209-214 “Oral spironolactone improves acne vulgaris and reduces    sebum excretion”-   Goulden, V.; Mcgeown, C. H.; Cunliffe, W. J. Brit. J. Dermatol.    1999, 141, 297-300 “Familial Risk of Adult Acne: A comparison    between first-degree relatives of affected and unaffected    individuals”-   Graefe, T.; Wollina, U.; Schulz, H.-J.; Burgdorf, W. Dermatology    2000, 200, 331-333 “Muir-Torre Syndrome—Treatment with Isotretinoin    and Interferon Alpha-2a Can Prevent Tumour Development”-   Griffon, N.; Mignon, V.; Facchinetti, P.; Diaz, J.; Schwartz, J.-C.;    Sokoloff, P. BBRC 1994, 200, 1007-1014 “Molecular cloning and    characterization of the rat fifth melanocortin receptor”-   Gupta, A. K.; Bluhm, R. Journal of the European Academy of    Dermatology and Venereology 2004 18:1 13 “Seborrheic dermatitis”-   Haitina, T.; Klovins, J.; Andersson, J.; Fredriksson, R.;    Lagerström, M. C.; Larhammar, D.; Larson, E. T.; Schiöth, H. B.    Biochem. J. 2004, 380, 475-486 “Cloning, tissue distribution,    pharmacology and three-dimensional modelling of melanocortin    receptors 4 and 5 in rainbow trout suggest close evolutionary    relationships of these subtypes”-   Harper, J. C. Semin. Cutan. Med. Surg. 2005, 24, 103-106 “Hormonal    Therapy for Acne using oral contraceptive pills-   Harris, H. H.; Downing, D. T.; Stewart, M. E.; Strauss, J. S. J. Am.    Acad. Dermatol. 1983, 8, 200-203 “Sustainable rates of sebum    secretion in acne patients and mayched normal controls”-   Hatta, N.; Dixon, C.; Ray, A. J.; Phillips, S. R.; Cunliffe, W. J.;    Dale, M.; Todd, C.; Meggit, S.; Birch-Machin, M. A.; Rees, J. L. J.    Invest. Dermatol. 2001, 116, 564-570 “Expression, candidate gene,    and population studies of the melanocortin 5 receptor”-   Houseknecht, K. L.; Robertson, A. S.; Xiao, X. US2003/0110518A1 Jun.    12, 2003 “Melanocortin-5 receptor sequences and uses thereof”-   Huang, R.-R. C.; Singh, G.; Van der Ploeg, L. H. T.; Fong, T. M. J.    Receptor & Signal Transduction Res. 2000, 20, 47-59    “Species-dependent pharmacological properties of the melanocortin-5    receptor”-   Ide, F.; Shimoyama, T.; Hone, N.; Kaneko, T.; Matsumoto, M. Oral    Surg. Oral Med. Oral Pathol. Oral Radiol. Endod. 1999, 87, 721-724    “Benign lymphoepithelial lesion of the parotid gland with sebaceous    differentiation”-   Jeong, S. K.; Hwang, S. W.; Choi, S. Y.; An, J. M.; Seo, J. T.;    Zouboulis, C. C.; Lee, S. H. J. Investigative Dermatol. 2007, 127,    pS72 “Intracellular calcium mobilization is mediated by the    melanocortin receptors in SZ95 sebocytes” (Abstract 431, Society for    Investigative Dermatology, May 2007, Los Angeles Calif.)-   Jih, M. H.; Friedman, P. M.; Goldberg, L. H.; Robles, M.; Glaich, A.    S.; Kimyai-Asadi, A. J. Am. Acad. Dermatol. 2006, 55, 80-87 “The    1450-nm diode laser for facial inflammatory acne vulgaris:    Dose-response and 12-month follow-up study”.-   Jones, D. H.; King, K.; Miller, A. J.; Cunliffe, W. J. Brit. J.    Dermatol. 1983, 108, 333-343 “A dose-response study of    13-cis-retinoic acid in acne vulgaris”-   Kim, K. S.; Marklund, S.; Rothschild, M. F. Animal Genetics 2000,    31, 230-231. “The porcine melanocortin-5-receptor (MC5R) gene:    polymorphisms, linkage and physical mapping”-   King, K.; Jones, D. H.; Daltrey, D. C.; Cunliffe, W. J. Brit. J.    Dermatol. 1982, 107, 583-590 “A double-blind study of the effects of    13-cis-retinoic acid on acne, sebum excretion rate and microbial    population”-   Kligman, A. M. Brit. J. Dermatol. 1963, 75, 307-319 “The uses of    sebum”-   Klovins, J.; Haitina, T.; Ringholm, A.; Löwgren, M.; Fridmanis, D.;    Slaidina, M.; Stier, S.; Schiöth, H. B. Eur. J. Biochem. 2004, 271,    4320-4331 “Cloning of two melanocortin (MC) receptors in spiny    dogfish”-   Kruse, R.; Rütten, A.; Schweiger, N.; Jakob, E.; Mathiak, M.;    Propping, P.; Mangold, E.; Bisceglia, M; Ruzicka, T. J. Invest.    Dermatol. 2003, 120, 858-864 “Frequency of Microsatellite    Instability in Unselected Sebaceous Gland Neoplasias and    Hyperplasias”-   Labbé, O.; Desarnaud, F.; Eggerickx, D.; Vassart, G.; Parmentier, M.    Biochem. 1994, 33, 4543-4549 “Molecular Cloning of a mouse    melanocortin 5 receptor gene widely expressed in peripheral tissues”-   Ling, M. K.; Hotta, E.; Kilianova, Z.; Haitina, T.; Ringholm, A.;    Johansson, L.; Gallo-Payet, N.; Takeuchi, S.; Schiöth, H. B.    Brit. J. Pharmacol. 2004, 143, 626-637 “The melanocortin receptor    subtypes in chicken have high preference to ACTH-derived peptides”-   Makrantonaki, E.; Zouboulis, C. C. Brit. J. Dermatol. 2007, 156,    428-432 “Testosterone metabolism to 5a-dihydrotestosterone and    synthesis of sebaceous lipids is regulated by the peroxisome    proliferator-activated receptor ligand linoleic acid in human    sebocytes”-   Mariappan, M. R.; Fadare, O.; Jain, D. Arch. Pathol. Lab. Med. 2004,    128, 245-246 “Sebaceous Differentiation in Salivary Glands”-   Mallon, E.; Newton, J. N.; Klassen, A.; Stewart-Brown, S. L.;    Ryan, T. J.; Finlay, A. Y. Brit. J. Dermatol. 1999, 140, 672-676    “The quality of life in acne: a comparison with general medical    conditions using generic questionnaires”-   Marqueling A. L.; Zane, L. T. Semin. Cutan. Med. Surg. 2005, 24,    92-102 “Depression and Suicidal Behavior in Acne Patients Treated    with Isotretinoin: A Systematic Review”-   Morgan, C.; Thomas, R. E.; Ma, W.; Novotny, M. V.; Cone, R. D. Chem.    Senses 2004a, 29, 111-115 “Melanocortin-5 receptor deficiency    reduces a pheromonal signal for aggression in male mice”-   Morgan, C.; Thomas, R. E.; Cone, R. D. Horm. Behav. 2004b, 45, 58-83    “Melanocortin-5 receptor deficiency promotes defensive behaviour in    male mice”-   Morgan, C.; Cone, R. D. Behaviour Genetics 2006, 36, 291-300    “Melanocortin-5 receptor deficiency in mice blocks a novel pathway    influencing pheromone-induced aggression”-   Mourelatos, K.; Eady, E. A.; Cunliffe, W. J.; Clark, S. M.;    Cove, J. H. Brit. J. Dermatol. 2007, 156, 22-31 “Temporal changes in    sebum excretion and propionibacterial colonization in preadolescent    children with and without acne”-   Nelson, A. M.; Gilliland, K. L.; Cong, Z.; Thiboutot, D. M. J.    Investigative Dermatol. 2006, 126, 2178-2189 “13-cis-Retinoic Acid    Induces Apoptosis and Cell Cycle Arrest in Human SEB-1 Sebocytes”-   Phan, J.; Kanchanapoomi, M.; Liu, P.; Jalian, H.; Gilliland, K.;    Nelson, A.; Thiboutot, D.; Kim, J. J. Investigative Dermatol. 2007,    127, pS126 “P. acnes induces inflammation via TLR2 and upregulates    antimicrobial activity in sebocytes” (Abstract 754, Society for    Investigative Dermatology, May 2007, Los Angeles Calif.)-   Piérard, G. E.; Piérard-Franchimont, T. L. Dermatologica 1987, 175,    5-9 “Seborrhoea in Acne-Prone and Acne-Free Patients”-   Plewig G, Jansen T. Seborrheic dermatitis. In: Freedberg I M, Eisen    A Z, Wolff K, Austen K F, Goldsmith L A, Katz S I, Fitzpatrick T B,    (Eds). Dermatology in General Medicine, 5th ed. New York:McGraw    Hill, 1999: 1482-1489-   Pochi, P. E.; Strauss, J. S. J. Invest. Dematol. 1964, 43, 383-388    “Sebum production, casual sebum levels, titratable acidity of sebum    and urinary fractional 17-ketosteroid excretion in males with acne”-   Porter, A. M. W. J. Royal Soc. Med. 2001, 94, 236-237 “Why do we    have apocrine and sebaceous glands”-   Ringholm, A.; Fredriksson, R.; Poliakova, N.; Yan, Y.-L.;    Postlethwait, J. H.; Larhammar, D.; Schiöth, H. B. J. Neurochem.    2002, 82, 6-18 “One melanocortin 4 and two melanocortin 5 receptors    from zebrafish show remarkable conservation in structure and    pharmacology”-   Shuster, S. Lancet 1976, 7973, 1328-1329 “Biological purpose of    acne”-   Simpson. N. B. and Cunliffe. W. J. in Rooks' Textbook of    Dermatology, 7^(th) Ed 2004 Blackwell Science, Malden Mass, p    43.1-43.75 “Chapter 43. Disorders of the Sebaceous Glands”.-   Smith, K. R.; Nelson, A.; Cong, Z.; Thiboutot, D. J. Investigative    Dermatol. 2007a, 127, pS68 “Iron status affects human sebocyte    survival” (Abstract 408, Society for Investigative Dermatology, May    2007, Los Angeles Calif.)-   Smith, R. N.; Mann, N. J.; Braue, A.; Makelainen, H.;    Varigos, G. A. J. Am. Acad. Dermatol. 2007b, 57, 247-256 “The effect    of a high-protein, low glycemic-load diet versus a conventional,    high glycemic-load diet on biochemical parameters associated with    acne vulgaris: A randomized investigator-masked, controlled trial”-   Taylor, A.; Namba, K. Immunologyy Cell Biol. 2001, 79, 358-367 “In    vitro induction of CD25+CD4+ regulatory T cells by the neuropeptide    alpha-melanocyte stimulating hormone (α-MSH)”-   Thiboutot, D.; Sivarajah, A.; Gilliland, K.; Cong, Z.;    Clawson, G. J. Invest. Dermatol. 2000, 115, 614-619 “The    melanocortin 5 receptor is expressed in human sebaceous glands and    rat preputial cells”-   Thody, A. J.; Shuster, S. Nature 1973, 245, 207-209 “Possible role    of MSH in the mammal”-   Thody, A. J.; Cooper, M. F.; Bowden, P. E.; Shuster, S. J.    Endocrinol. 1975a, 67, 18P-19P “The sebaceous gland response to    α-melanocyte-stimulating hormone and testosterone”-   Thody, A. J.; Shuster, S. J. Endocrinol. 1975b, 64, 503-510 “Control    of sebaceous gland function in the rat by α-melanocyte-stimulating    hormone”-   Thody, A. J.; Goolamali, S. K.; Burton. J. L; Plummer, N. A.;    Shuster, S. Brit. J. Dermatol. 1975c, 92, 43-47 “Plasma β-MSH levels    in acne vulgaris”-   Wikberg, J. E. S. Exp. Opin. Ther. Patents 2001, 11, 61-76    “Melanocortin receptors: new opportunities in drug discovery”;-   Wikberg, J.; Chhajlani, V. US6448032B1 Sep. 10, 2002 “Human    melanocyte stimulating hormone receptor polypeptide and DNA”-   Williams, C.; Layton, A. M. Exp. Rev. Dermatol. 2006, 1, 429-438    “Treatment of Acne: an update”-   Yamada, T.; Gantz, I. U.S. Pat. No. 5,622,860, Apr. 22, 1997, “Genes    Encoding Melanocortin Receptors”-   Yaswen, L.; Diehl, N.; Brennan, M. B.; Hochgeschwender, U. Nature    Med. 1999, 5, 1066-1070 “Obesity on the mouse model of    pro-opiomelanocortin deficiency responds to peripheral melanocortin”-   Youn, S.-W.; Park, E.-S.; Lee, D.-H.; Huh, C.-H.; Park, K.-C.    Brit. J. Dermatol. 2005, 153, 919-924 “Does facial sebum secretion    really affect the development of acne?”-   Zhang, L.; Anthonavage, M.; Huang, Q.; Li, W.-H.; Eisinger, M. Ann.    N.Y. Acad. Sci. 2003, 994, 154-161 “Proopiomelanocortin peptides and    sebogenesis”-   Zhang, L.; Li, W.-H.; Anthonavage, M.; Eisinger, M. Peptides 2006,    27, 413-420 “Melanocortin-5 receptor: a marker of human sebocyte    differentiation”-   Zouboulis, C. C.; Böhm, M. Exp. Dermatol. 2004, 13, 31-35    “Neurocrine regulation of sebocytes—a pathogenetic link between    stress and acne”    The details of specific embodiments described in this invention are    not to be construed as limitations. Various equivalents and    modifications may be made without departing from the essence and    scope of this invention, and it is understood that such equivalent    embodiments are part of this invention.

1. A compound of formula (I):

wherein: Y is a group of formula —(CR⁹R¹⁰)_(n)—; X is selected from thegroup consisting —C(═O)—, —OC(═O)—, —NHC(═O)—, —(CR¹¹R¹²)_(s), and—S(═O)₂—; Z is a group of formula —(CR¹³R¹⁴)_(q)—; R¹ is selected fromthe group consisting of H, optionally substituted C₁-C₁₂alkyl,optionally substituted C₂-C₁₂alkenyl, optionally substitutedC₂-C₁₂alkynyl, optionally substituted C₂-C₁₄heteroalkyl, optionallysubstituted C₃-C₁₂cycloalkyl, optionally substituted 3 to 10 memberedheterocycloalkyl, optionally substituted C₆-C₁₈aryl, and optionallysubstituted heteroaryl; R² and R³ are each independently selected fromthe group consisting of H, optionally substituted C₁-C₁₂alkyl,optionally substituted C₂-C₁₂alkenyl, optionally substitutedC₂-C₁₂alkynyl, optionally substituted C₂-C₁₄heteroalkyl, optionallysubstituted C₃-C₁₂cycloalkyl, optionally substituted 3 to 10 memberedheterocycloalkyl, optionally substituted C₆-C₁₈aryl, and optionallysubstituted heteroaryl; R^(4a) is selected from the group consisting ofH, optionally substituted C₁-C₁₂alkyl, optionally substitutedC₂-C₁₂alkenyl, optionally substituted C₂-C₁₂alkynyl, optionallysubstituted C₂-C₁₄heteroalkyl, optionally substituted C₃-C₁₂cycloalkyl,optionally substituted 3 to 10 membered heterocycloalkyl, optionallysubstituted C₆-C₁₈aryl, optionally substituted heteroaryl, C(═O)R¹⁵,C(═O)NR¹⁵R¹⁶, C(═O)OR¹⁵, SO₂R¹⁵, C(═O)H, —C(═NR¹⁵)—NR¹⁶R¹⁷, and OR¹⁵,R^(4b) is selected from the group consisting of H, optionallysubstituted C₁-C₁₂alkyl, optionally substituted C₂-C₁₂alkenyl,optionally substituted C₂-C₁₂alkynyl, optionally substitutedC₂-C₁₄heteroalkyl, optionally substituted C₃-C₁₂cycloalkyl, optionallysubstituted 3 to 10 membered heterocycloalkyl, optionally substitutedC₆-C₁₈aryl, optionally substituted heteroaryl, C(═O)R¹⁵, C(═O)NR¹⁵R¹⁶,C(═O)OR¹⁵, or R^(4a) and R^(4b) when taken together with the nitrogenatom to which they are attached form an optionally substituted 3 to 10membered heterocycloalkyl and optionally substituted heteroaryl, or oneof R^(4a) and R^(4b) when taken together with any R¹³ or R¹⁴ and theatoms to which they are attached forms an optionally substituted 3 to 10membered heterocycloalkyl and optionally substituted heteroaryl; eachR^(5a) and R^(5b) are independently selected from the group consistingof H, halogen, C₁-C₁₂alkyl, C₁-C₁₂hydroxyalkyl and C₁-C₁₂haloalkyl, orone or more of R^(5a) and R^(5b) when taken together with one or more ofR⁶, R⁷ and R⁸ and the atoms to which they are attached form a moietyselected from the group consisting of an optionally substitutedC₃-C₁₂cycloalkyl, optionally substituted 3 to 10 memberedheterocycloalkyl, optionally substituted C₆-C₁₈aryl, and optionallysubstituted heteroaryl; R⁶, R⁷ and R⁸ are each independently selectedfrom the group consisting of H, halogen, hydroxy, optionally substitutedC₁-C₁₂alkyl, optionally substituted C₂-C₁₂alkenyl, optionallysubstituted C₂-C₁₂alkynyl, optionally substituted C₂-C₁₄ heteroalkyl,optionally substituted C₁-C₁₀ heteroalkenyl, optionally substitutedC₃-C₁₂cycloalkyl, optionally substituted 3 to 10 memberedheterocycloalkyl, optionally substituted C₆-C₁₈aryl, optionallysubstituted heteroaryl, optionally substituted amino, optionallysubstituted carboxy, and C₁-C₁₂alkyloxy, or (a) when taken together withthe carbon atom to which they are attached two or more of R⁶, R⁷ and R⁸form a moiety selected from the group consisting of optionallysubstituted C₂-C₁₂alkenyl, optionally substituted C₃-C₁₂cycloalkyl,optionally substituted 3 to 10 membered heterocycloalkyl, optionallysubstituted C₆-C₁₈aryl, and optionally substituted heteroaryl, or (b)one or more of R⁶, R⁷ and R⁸ when taken together with one or more ofR^(5a) and R^(5b) and the atoms to which they are attached form a moietyselected from the group consisting of an optionally substitutedC₃-C₁₂cycloalkyl, optionally substituted 3 to 10 memberedheterocycloalkyl, optionally substituted C₆-C₁₈aryl, and optionallysubstituted heteroaryl; each R⁹ and R¹⁰ is independently selected fromthe group consisting of H and optionally substituted C₁-C₁₂alkyl; eachR¹¹ and R¹² is independently selected from the group consisting of H,and optionally substituted C₁-C₁₂alkyl; R¹³ and R¹⁴ are eachindependently selected from the group consisting of H, halogen, OH,C₁-C₁₂alkyl, C₆-C₁₈aryl, C₁-C₁₂haloalkyl, C₁-C₁₂hydroxyalkyl,C₁-C₁₂alkyloxy and C₁-C₁₂haloalkyloxy, or when taken together with thecarbon to which they are attached R¹³ and R¹⁴ form an optionallysubstituted C₃-C₁₂cycloalkyl, or an optionally substituted 3 to 10membered heterocycloalkyl group; each R¹⁵, R¹⁶, and R¹⁷ is independentlyselected from the group consisting of H, optionally substitutedC₁-C₁₂alkyl, optionally substituted C₂-C₁₄heteroalkyl, optionallysubstituted C₃-C₁₂cycloalkyl, optionally substituted C₆-C₁₈aryl, andoptionally substituted heteroaryl, or any two of R¹⁵, R¹⁶ and R¹⁷ whentaken together with the atoms to which they are attached form anoptionally substituted 3 to 10 membered heterocycloalkyl n is an integerselected from the group consisting of 1, 2, 3 and 4; q is an integerselected from the group consisting of 0, 1, 2, 3, 4, and 5; r is aninteger selected from the group consisting of 1, 2, 3, and 4; s is aninteger selected from the group consisting of 1, 2, 3, and 4; whereineach optional substituent is independently selected from the groupconsisting of F, Cl, Br, I, CH₃, CH₂CH₃, OH, OCH₃, CF₃, OCF₃, NO₂, NH₂,and CN; wherein each C₂-C₁₄ heteroalkyl and each 3 to 10 memberedheterocycloalkyl contains from 1 to 3 heteroatoms selected fromnitrogen, sulfur, or oxygen; and wherein each heteroaryl isindependently selected from the group consisting of thiophenyl,benzotriazolyl, benzothiophenyl, benzofuranyl, benzimidazolyl,benzoxazolyl, benzothiazolyl, benzisothiazolyl, naptho[2,3-b]thiophenyl,furanyl, isoindolizinyl, xantholenyl, phenoxatinyl, pyrrolyl,imidazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl,tetrazolyl, indolyl, isoindolyl, 1H-indazolyl, purinyl, quinolonyl,isoquinolinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, cinnolinyl,carbazolyl, phenanthridinyl, acridinyl, phenazinyl, thiazolyl,isothiazolyl, phenothiazinyl, oxazolyl, isooxazlyl, furazanyl,phenoxazinyl, 2-, 3- or 4-pyridyl, 2-, 3-, 4-, 5-, or 8- quinolyl, 1-,3-, 4-, or 5-isoquinolinyl, 1-, 2-, or 3-indolyl, and 2- or 3-thienyl;or a pharmaceutically acceptable salt thereof.
 2. A compound accordingto claim 1 wherein R¹ is selected from the group consisting of (a)optionally substituted C₆-C₁₈ aryl wherein the C₆-C₁₈ aryl is phenyl,biphenyl, or napthyl; (b) optionally substituted heteroaryl wherein theheteroaryl is indol-2-yl, indol-3-yl, quinolin-2-yl, quinolin-3-yl,isoquinolin-3-yl, quinoxaline-2-yl, benzo[b]furan-2-yl,benzo[b]thiophen-2-yl, benzo[b]thiophen-5-yl, thiazole-4-yl,benzimidazole-5-yl, benzotriazol-5-yl, furan-2-yl,benzo[d]thiazole-6-yl, pyrazole-1-yl, pyrazole-4-yl or thiophen-2-yl;and (c) optionally substituted alkenyl of the formula:

wherein R^(1c) is optionally substituted C₆-C₁₈ aryl wherein the C₆-C₁₈aryl is selected from phenyl and naphthyl; R² and R³ are each H or C₁-C₆alkyl; R^(4a) is selected from the group consisting of H, —C(═NH)NH₂,—C(═NH)N(CH₃)₂, —C(═NH)NHCH(CH₃)₂, —C(═O)CH₃, —C(═O)cyclohexyl, CH₃,CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₂CH₃, —CH(CH₃)CH₂CH₃, CH₂CH(CH₃)₂,C(CH₃)₃, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, andphenyl, or a halogenated derivative thereof, R^(4b) is selected from thegroup consisting of H, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₂CH₃,CH(CH₃)CH₂CH₃, CH₂CH(CH₃)₂, C(CH₃)₃, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, benzyl, and phenyl, or a halogenated derivativethereof, or (a) R^(4a) and R^(4b) when taken together with the nitrogenatom to which they are attached form an optionally substituted 3 to 10membered heterocycloalkyl group selected from the group consisting ofpiperidinyl, pyrrolidinyl, azepanyl, azetidinyl, morpholinyl, andpiperazinyl, or (b) one of R^(4a) and R^(4b) when taken together withthe nitrogen atom to which it is attached and one of R¹³ and R¹⁴ and thecarbon atom to which it is attached form an optionally substituted 3 to10 membered heterocycloalkyl group selected from the group consisting ofpiperidinyl, pyrrolidinyl, azepanyl, azetidinyl, morpholinyl, andpiperazinyl; R⁶ and R⁸ are each independently selected from the groupconsisting of H, optionally substituted C₁-C₁₂-alkyl, optionallysubstituted-C₂-C₁₂ alkenyl, optionally substituted-C₆-C₁₈ aryl andoptionally substituted heteroaryl; and R⁷ is H; or (a) R⁶, R⁷ and R⁸when taken together with the carbon to which they are attached form amoiety selected from the group consisting of optionally substitutedC₂-C₁₂alkenyl, optionally substituted C₃-C₁₂cycloalkyl, optionallysubstituted 3 to 10 membered heterocycloalkyl, optionally substitutedC₆-C₁₈aryl, and optionally substituted heteroaryl; or (b) one or more ofR⁶, R⁷ and R⁸ when taken together with one or more of R^(5a) and R^(5b)and the atoms to which they are attached form a moiety selected from thegroup consisting of an optionally substituted C₃-C₁₂cycloalkyl,optionally substituted 3 to 10 membered heterocycloalkyl, optionallysubstituted C₆-C₁₈aryl, and optionally substituted heteroaryl; or apharmaceutically acceptable salt thereof.
 3. A compound according toclaim 2 wherein R^(5a) and R^(5b) are each independently H or C₁-C₆alkyl; R⁶, R⁷ and R⁸ are each independently H, methyl, trifluoromethyl,ethyl, 2,2,2-trifluoroethyl, isopropyl, isopropenyl, propyl,2-ethyl-propyl, 3,3-dimethyl-propyl, butyl, 2-methylbutyl, isobutyl,3,3-dimethyl-butyl, 2-ethyl-butyl, pentyl, 2-methyl-pentyl, optionallysubstituted phenyl or optionally substituted heteroaryl wherein theheteroaryl is thiophene, furan, pyrrole, imidazole, pyrazole, pyridine,pyrazine, or tetrazole; R¹³ and R¹⁴ are each independently H or C₁-C₆alkyl; or a pharmaceutically acceptable salt thereof.
 4. A compoundaccording to claim 3 wherein X is —C(═O)—; Y is CH₂; Z is —(CH₂)_(q)—;R^(5a) is H; R^(5b) is H; r is 1; q is 1, 2, 3, or 4; or apharmaceutically acceptable salt thereof.
 5. A compound according toclaim 4 wherein R^(4a) is H, —C(═NH)NH₂, —C(═NH)N(CH₃)₂,—C(═NH)NHCH(CH₃)₂, —C(═O)CH₃, —C(═O)cyclohexyl, CH₃, CH₂CH₃, CH₂CH₂CH₃,CH(CH₃)₂, CH₂CH₂CH₂CH₃, —CH(CH₃)CH₂CH₃, CH₂CH(CH₃)₂, C(CH₃)₃,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, and phenyl, ora halogenated derivative thereof and R^(4b) is H, CH₃, CH₂CH₃,CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₂CH₃, CH(CH₃)CH₂CH₃, CH₂CH(CH₃)₂, C(CH₃)₃,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, and phenyl, ora halogenated derivative thereof; or a pharmaceutically acceptable saltthereof.
 6. A compound according to claim 4 wherein R^(4a) and R^(4b)when taken together with the nitrogen atom to which they are attachedform an optionally substituted 3 to 10 membered heterocycloalkyl groupselected from the group consisting of piperidinyl, pyrrolidinyl,azepanyl, azetidinyl, morpholinyl, and piperazinyl; or apharmaceutically acceptable salt thereof.
 7. A compound according toclaim 5 wherein R¹ is an optionally substituted C₆-C_(l8)aryl selectedfrom the group consisting of optionally substituted phenyl andoptionally substituted naphthyl; or a pharmaceutically acceptable saltthereof.
 8. A compound according to claim 6 wherein R¹ is an optionallysubstituted C₆-C₁₈aryl selected from the group consisting of optionallysubstituted phenyl and optionally substituted naphthyl; or apharmaceutically acceptable salt thereof.
 9. A compound according toclaim 1 wherein R¹ is an optionally substituted C₂-C₁₂alkenyl of theformula:

R^(1a) is selected from the group consisting of H, halogen andoptionally substituted C₁-C₁₂ alkyl; R^(1b) and R^(1c) are eachindependently selected from the group consisting of H, halogen,optionally substituted C₁-C₁₂alkyl, optionally substitutedC₂-C₁₂alkenyl, optionally substituted C₂-C₁₂alkynyl, optionallysubstituted C₂-C₁₄heteroalkyl, optionally substituted C₃-C₁₂cycloalkyl,optionally substituted 3 to 10 membered heterocycloalkyl, optionallysubstituted C₆-C₁₈aryl, and optionally substituted heteroaryl; or apharmaceutically acceptable salt thereof.
 10. A compound according toclaim 9 wherein R^(1a) is H; R^(1b) is H; and R^(1c) is optionallysubstituted C₆-C₁₈aryl; or a pharmaceutically acceptable salt thereof.11. A compound according to claim 10 wherein R^(1c) is optionallysubstituted phenyl; or a pharmaceutically acceptable salt thereof.
 12. Acompound according to claim 9 wherein R^(ia) is H; R^(1b) is H; andR^(1c) is optionally substituted C₆-C₁₈aryl; or a pharmaceuticallyacceptable salt thereof.
 13. A compound according to claim 12 whereinR^(1c) is optionally substituted phenyl; or a pharmaceuticallyacceptable salt thereof.
 14. A compound according to claim 8 wherein qis 1 or 2; or a pharmaceutically acceptable salt thereof.
 15. A compoundaccording to claim 14 wherein R⁶, and R⁸ are each independently H,methyl, ethyl, or phenyl; and R⁷ is H; or a pharmaceutically acceptablesalt thereof.
 16. A pharmaceutical composition comprising a compoundaccording to claim 1 or a pharmaceutically acceptable salt thereof, anda pharmaceutically acceptable carrier, diluent or excipient.